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Insights into pathogenic events of HIV-associated Kaposi sarcoma and immune reconstitution syndrome related Kaposi sarcoma

Insights into pathogenic events of HIV-associated Kaposi sarcoma and immune reconstitution... A decrease in the incidence of human immune deficiency virus-associated Kaposi sarcoma (HIV- KS) and regression of some established HIV-KS lesions is evident after the introduction of highly active anti-retroviral treatment (HAART), and is attributed to generalized immune restoration, to the reconstitution of human herpesvirus (HHV)-8 specific cellular immune responses, and to the decrease in HIV Tat protein and HHV-8 loads following HAART. However, a small subset of HIV- seropositive subjects with a low CD4+ T cell count at the time of introduction of HAART, may develop HIV-KS as immune reconstitution inflammatory syndrome (IRIS) within 8 weeks thereafter. commonly by proximal lymph node involvement [9]. The Introduction Kaposi sarcoma (KS) is the most common human immu- pathogenesis of HIV-KS is complex, and involves interac- nodeficiency virus (HIV)-associated neoplasm [1]. HIV- tion between human herpesvirus (HHV)-8, HIV, inflam- associated Kaposi sarcoma (HIV-KS) lesions are character- matory cytokines, and angiogenic factors in the presence ized microscopically by angiogenesis, the presence of of profound immune suppression [10-12]. However, the spindle-shaped tumour cells, inflammatory cell infiltrates understanding of how these multiple factors interplay to dominated by mononuclear cells, extravasated erythro- initiate KS is incomplete [3]. cytes and oedema [2-4]. Clinically, HIV-seropositive sub- jects with KS exhibit mainly multifocal mucocutaneous HHV-8 is present in all four epidemiological forms of KS patches, plaques and nodules, and less frequently organ (classic, endemic, iatrogenic and HIV-KS). Seroprevalence involvement [5-7]. The most common site of extra-muco- studies demonstrate that HHV-8 DNA in peripheral blood cutaneous HIV-KS involvement is the lymph nodes fol- mononuclear cells (PBMC) and specific antibodies to lowed by the gastro-intestinal tract and the lungs. The oral HHV-8 are associated with increased risk of KS, and there cavity is commonly affected and is the initial site of is a positive correlation between the HHV-8 viral load and involvement with KS in about 20% of HIV-seropositive the severity of KS. These lines of evidence indicate that subjects with KS [8]. Oedema is a major clinical feature HHV-8 is necessary for the development of KS, but since associated with advanced KS. It results most frequently HHV-8 seroconversion in the general population is not when a local inflammatory reaction induced by produc- uncommon and is much more common in HIV-seroposi- tion of cytokines by KS cells is complicated either by lym- tive subjects, but yet only some members of these popula- phatic obstruction by the enlarging tumour itself, or less Page 1 of 9 (page number not for citation purposes) Infectious Agents and Cancer 2008, 3:1 http://www.infectagentscancer.com/content/3/1/1 tions develop KS, other co-factors are clearly necessary for become nodular and may have an aggressive clinical the development of KS [13-29]. behaviour [60,61]. HIV contributes to the pathogenesis of KS through several The late-stage maculo-papular HIV-KS lesions are charac- mechanisms: HIV Tat protein directly promotes HHV-8 terized by proliferation of spindle cells, of lymphatic and/ replication [30,31]; HIV induces the production of or blood vascular endothelial origin. The spindle cells inflammatory cytokines [12,32], and causes a profound become the predominant cell type, though the vascular immune impairment that is conducive to the develop- element is always evident [23,65,66]. The progression of ment of KS. The incidence and aggressiveness of KS is sub- HIV-KS is attributed to dysregulation in cell cycle growth stantially increased in HIV-seropositive subjects and resistance to apoptotic signals mediated by altered compared to HIV-seronegative subjects [10,31,32]. This cytokine networks, latent and dysregulated lytic HHV-8 emphasizes the important role of HIV in the natural genes and HIV Tat protein [3,67]. course of HIV-KS. Early-stage HIV-KS is a polyclonal reactive angioprolifera- The use of highly active antiretroviral therapy (HAART) tive disorder. This is evident from the multifocal charac- has resulted in a dramatic reduction in the morbidity and teristic of the HIV-KS lesions in the absence of metastasis; mortality in HIV-seropositive subjects [33-36]. HAART, by the occasional regression of HIV-KS lesions either although not directly affecting HHV-8 replication, indi- spontaneously or following the introduction of HAART; rectly brings about a decrease in HHV-8 viral load [37], a and by the lack of clonality [68]. In contrast, late stage substantial reduction in the prevalence and incidence of HIV-KS lesions from disparate subjects may show a spec- HIV-KS [38-42], and improvement in the clinical manifes- trum of multiclonal origin, monoclonality, oligoclonality tation of KS [43-52]. and polyclonality, and it is likely that a subset of late-stage lesional cells of monoclonal origin undergo malignant However, HAART does not ensure that KS will not transformation [69,70]. develop, and in subjects receiving HAART, KS remains the most frequent HIV-associated neoplasm [5,53]. HIV-sero- Most of HIV-KS spindle cells express HHV-8 latent genes, positive subjects who had already received HAART at the but not genes that are involved in lytic reactivation and time of KS diagnosis, usually have less aggressive KS dis- replication of latently infected cells. However, some of the ease compared to HIV-seropositive subjects who were virally infected KS cells express HHV-8 lytic genes, that HAART naïve at the time of KS diagnosis [5,54]. In addi- provide paracrine angioproliferative inductive signals to tion, KS sometimes recrudesces as an immune reconstitu- neighbouring endothelial and spindle cells mediating tion inflammatory syndrome (IRIS) in HIV-seropositive angiogenesis and spindle cell proliferation [23]. subjects shortly after the introduction of HAART, despite an improvement in the CD4+ T cell count and controlled The persistent endothelial and spindle cell proliferation, HIV viremia [55-60]. in response to HHV-8 induced inflammatory and growth factors, and to HHV-8 oncogenes leads to dysregulated cell proliferation and survival, followed by cellular trans- The natural course of HIV-KS There is a compelling body of information that supports formation and eventual progression to a monoclonal the concept that HIV-KS is an opportunistic tumour that tumour [12,13,23]. The malignant transformation of HIV- starts as a reactive hyperplasia and eventually may KS cells, when and if it occurs, is probably driven by HHV- progress to a true neoplasia [12,13,16,23,60-64]. 8 latent oncogenes and by the dysregulated constitutive activity of viral G protein-coupled receptor (vGPCR) HIV-KS has its origin in an environment induced by expressed outside the lytic phase of the virus replication inflammatory T helper (Th)-1 cytokines associated with a cycle, without notable cellular genetic and epigenetic marked impairment of cellular immune responses, mutation of cell cycle genes and/or tumour suppressor brought about by HIV infection. The inflammatory infil- genes [3,62]. trate in HIV-KS lesions comprise CD8+ T cells, monocytes, macrophages and dendritic cells. These cells produce The implication of inflammatory cytokines in the inflammatory cytokines that together with HHV-8 gene pathogenesis of HIV-KS products, activate endothelial cells and trigger the devel- The pathogenesis of HIV-KS is related to infection with opment of HIV-KS. Early HIV-KS lesions manifest clini- HHV-8 and HIV, and to persistent inflammation in the cally as indolent red-purple macules or papules, that show presence of high level of Th1-type inflammatory cytokines proliferation of endothelial cells and formation of slit- including tumour necrosis factor (TNF)-α, interferon shaped vascular channels resembling well vascularized (INF)-γ, interleukin (IL)-1β, and IL-6, within an environ- exuberant granulation tissue. In time, HIV-KS lesions ment of immunosuppression. Increased HIV and HHV-8 Page 2 of 9 (page number not for citation purposes) Infectious Agents and Cancer 2008, 3:1 http://www.infectagentscancer.com/content/3/1/1 loads and concurrent opportunistic infections only serve greater aggressiveness in clinical behaviour of HIV-KS to perpetuate the inflammatory state [60,71]. It is proba- compared to other epidemiological forms of KS. ble that the increased level of inflammatory and ang- iogenic cytokines in all epidemiological forms of KS is the The role of bFGF and VEGF in the pathogenesis consequence of the local host immune activation against of HIV-KS HHV-8 and the HHV-8 release of cytokines in response to VEGF and bFGF are angiogenic growth factors that are the output of the HHV-8 genes [11,13]. powerfully expressed in HIV-KS lesions and promote ang- iogenesis. Both induce MMPs production by endothelial High levels of inflammatory cytokines in early KS lesions cells, and vascular permeability and subsequently oedema trigger endothelial cells to express activation markers that is an important feature of HIV-KS [74,78]. bFGF is including vascular cell adhesion molecules, matrix metal- produced by immunoregulatory cells, that are present in loproteinase (MMP), α β and αVβ integrins, growth fac- HIV-KS lesions, and by activated endothelial cells [79,80]. 5 1 3 tors such as vascular endothelial growth factor (VEGF) bFGF has an instrumental role in the development of HIV- and basic fibroblast growth factor (bFGF), and inflamma- KS. It can initiate and sustain neovascularization by pro- tory and angiogenic cytokines acting in both paracrine viding mitogenic signals to activated endothelial cells and and autocrine manner. These activated endothelial cells spindle cells [32,60,81]. This concept is supported by acquire abnormal phenotypic and functional features reports that the expression of bFGF is upregulated in HIV- (angiogenic phenotype) that may initiate and promote KS spindle cells, and antibodies to bFGF mRNA substan- the development of HIV-KS [61]. tially reduce the angiogenic and proliferative potential of HIV-KS cells [71]. In HIV-seropositive subjects with KS, Inflammatory cytokines have the capacity to reactivate bFGF mediates Tat-induced endothelial cell proliferation, latent HHV-8, resulting in an increase of HHV-8 plasma and acts with HIV Tat in promoting the production of load and spread of HHV-8 in tissues, and to promote HIV MMPs by endothelial cells[72,82]. replication, leading to a further production of HIV Tat protein and deterioration in host immune responses. VEGF is a potent specific endothelial cell mitogen pro- Thus, inflammatory cytokines have the potential to per- duced by HIV-KS endothelial and spindle cells in response petuate an environment conducive to HIV-KS initiation to inflammatory cytokines that induce angiogenesis and progression [61]. through autocrine mechanisms [23,83]. VEGF can syner- gise with bFGF to induce vascular permeability and α β and αVβ integrins oedema, and angiogenesis [13,23], and it is expressed and 5 1 3 The interactions between cells and extracellular matrix upregulated by several HHV-8 proteins including vIL-6 molecules (ECM) are mediated by cell membrane recep- and vGPCR and plays a significant part in the develop- tors belonging to the integrin family, that mediate cellular ment of KS [65]. migration and growth [72,73]. The increased levels of inflammatory cytokines and bFGF found in HIV-KS MMPs lesions upregulate the expression of α β and αVβ MMPs are a family of proteolytic enzymes involved in 5 1 3 integrins on HIV-KS cells [74]. degradation of extracellular matrix and basement mem- brane components. MMP gene expression is induced by a In HIV-seropositive subjects, extracellular HIV Tat protein variety of stimuli including inflammatory cytokines, binds to α β and αVβ integrin receptors on KS endothe- ECM-integrin interaction, growth factors, HIV Tat protein 5 1 3 lial and spindle cells, to provide them with the necessary and HHV-8 proteins [13,65,75]. MMP-2 is upregulated in signals for adhesion that is required for their subsequent HIV-KS lesions and it may play a rôle in inducing vascular proliferation in response to mitogenic stimuli by bFGF. permeability and oedema and in promoting endothelial HIV Tat protein also induces the synthesis of MMP-2 and cell growth, angiogenesis and tumour invasion MMP-9. The increased expression of MMPs in HIV-KS [74,84,85]. cells may lead to degradation of extracellular matrix com- ponents, facilitating the locomotion of endothelial cells Oxidative and nitrative metabolites in the and invasion of spindle cells [61,74,75]. pathogenesis of HIV-KS Persistent inflammatory state is conducive to the produc- In HIV-seronegative subjects with KS, cellular growth and tion of ongoing reactive oxidative and nitrative metabo- migration, and the expression of MMPs are induced by lites which are associated with tumourgenesis. They (α β )-fibronectin and (αVβ )-vitronectin interactions in promote cell proliferation, initiate nuclear and mitochon- 5 1 3 the presence of bFGF. The presence of HIV Tat protein in drial DNA mutations, induce a proangiogenic environ- HIV-KS fortifies the α β and αVβ stimulation [76,77]. ment, and inactivate DNA repair enzymes [71,86]. 5 1 3 This might explain the increased frequency of KS and the Page 3 of 9 (page number not for citation purposes) Infectious Agents and Cancer 2008, 3:1 http://www.infectagentscancer.com/content/3/1/1 HIV-seropositive subjects have high tissue levels of reac- secondly, HHV-8 specific – CD8 + cytotoxic T lymphocyte tive oxidative and nitrative metabolites owing to response is improved following HAART [13,88,89] and increased levels of proinflammatory cytokines, more fre- therefore there is a reduction in HHV-8 load. Thirdly, quent opportunistic infections and a reduction in the some protease inhibitors that are administered as a com- activity of antioxidant enzymes [87]. HIV-KS lesional cells ponent of HAART have anti-inflammatory and anti-ang- express endogenous oxidative and nitrative metabolites iogenic activity, thus directly inhibiting HIV-KS [10]. which together with increased exogenous oxidative and nitrative metabolite levels, associated with HIV infection, However, despite otherwise effective HAART, established may promote the particular aggressiveness of KS in HIV- HIV-KS may not always regress, and new KS lesions may seropositive subjects [71]. appear [13,54], perhaps as a manifestation of immune reconstitution inflammatory syndrome (IRIS) [30,33,55,56,59]. HIV infection, HAART and KS HIV infection may directly and indirectly promote the ini- tiation and progression of KS. HIV Tat protein, a transcrip- HIV associated IRIS IRIS can be defined as an exuberant immune-mediated tional activator of HIV gene expression, is a major factor implicated in the pathogenesis of HIV-KS [82]. Tat protein inflammatory response to a pre-existing subclinical path- is released by HIV-infected T cells. In this extracellular ogen or tumour antigen after treatment has brought about form, Tat synergises with inflammatory cytokines, which an improvement in a host previously profoundly are upregulated in HIV-KS lesions, to promote angiogen- depressed immunity [55,59,90]. In the context of HIV esis, and progression of HIV-KS. It does this by the induc- infection, HAART-induced IRIS has been described in rela- tion and mobilization of bFGF, and by interacting with tion to opportunistic infections including herpes simplex α β and αVβ integrins on both endothelial and spindle (HS), herpes zoster (HZ), mycobacterium tuberculosis, in 5 1 3 cells [75,80]. The coordinated signalling to endothelial relation to autoimmune thyroid disease, and in relation cells integrins α β and αVβ and growth factor receptors to KS. HIV-IRIS occurs paradoxically despite a reduction 5 1 3 by Tat protein and bFGF respectively, are important events in HIV load and improvement in all HIV related immuno- in the pathogenesis of HIV-KS [12,76]. logic parameters early after the introduction of HAART, and is probably the result of reconstituted pathogen-spe- By binding to α β and αVβ integrins on inflammatory cific immune responses [33,89,91-96]. However, the 5 1 3 cytokine-activated endothelial cells, Tat protein activates details regarding the immunopathogenic mechanisms the cascade of events in the FAS-ERK-MAPK intracellular that bring about IRIS are speculative [96]. signal transduction pathway. This promotes the progres- sion of KS endothelial cells through the G1 cell cycle In HIV-seropositive subjects who start HAART at an early phase in response to bFGF stimulation, and results in stage of HIV infection, the number and function of CD4+ increased cell proliferation [76]. In addition, Tat protein T cells tend to return to normal. On the other hand, sub- may act as an antiapoptotic agent causing prolonged sur- jects who start HAART, when the HIV infection is moder- vival of endothelial cells [67]. It also has the capacity to ately advanced (CD4+ T cell counts are between 100 × 6 6 regulate the cycle of HHV-8 growth and to reactivate latent 10 /L and 300 × 10 /L), will not show a similar recovery. HHV-8 infection [9,13]. A further outcome of the activity However, even such a partial immune reconstitution of Tat protein can be an increase in the synthesis of MMP- results in a profound decline in HIV-associated morbidity 2 by monocytes and by endothelial cells leading to and mortality [97]. increased vascular permeability and oedema [74]. CD4+ T cell restoration in peripheral blood after HAART HIV infection may indirectly affect the course of HIV-KS is biphasic. An initial rapid increase during the first 12 by perpetuating immunosuppression and immunodys- weeks of treatment is followed by a more gradual increase regulation, characterized by increased production of over the remainder of the first year, and after that there is proinflammatory cytokines that sustain the KS [13]. usually no further significant improvement. The initial- Moreover, Tat protein induces in monocyte-derived den- phase increase in the CD4+ T cells is due to proliferation dritic cells an increase in production of Th1 type cytokines and reduced apoptosis of existing memory cells in the cir- and β chemokines [77]. culation and to redistribution of CD4+ T cells from the lymph nodes into the circulation. Only after several Following the introduction of HAART sometimes estab- months of HAART, will T lymphoiesis associated with lished HIV-KS may regress and the likelihood of develop- improvement of thymic function become evident, giving ing new lesions of KS is diminished [5,9,13,38,40]. This rise to increased numbers of naïve T lymphocytes [89,97- can be attributed to three factors. Firstly, the reduction in 105]. With continued HAART there will also be an HIV load, Tat protein and inflammatory cytokines [13], increase in CD8+ T cells in the circulation lagging behind Page 4 of 9 (page number not for citation purposes) Infectious Agents and Cancer 2008, 3:1 http://www.infectagentscancer.com/content/3/1/1 the peak increase in CD4+ T cells by a period of about 5 opment of HIV-KS. The decline in the incidence of HIV- weeks. During the initial immune reconstitution phase KS, and the regression of KS in some HIV-seropositive the ability of the host to mount immuno-inflammatory subjects after the introduction of HAART, suggests that responses is restored [33,106], owing to the partial recov- some general improvement in immunity and in the recov- ery of CD4+ T cells and CD8+ cytotoxic T cell responses, ery of HHV-8-specific, MHC class I-restricted cytotoxic and the shift from a Th-2- to a Th-1-dominant cytokine CD8+ T cell response could be important in the control of profile. HHV-8 replication [114,115]. The CD4+ and CD8+ T cells that increase shortly after the introduction of HAART are All HIV-IRIS events occur in subjects who display as indi- memory cells. It is probable that in HIV-seropositive sub- cators of immune reconstitution, a decrease in HIV viral jects who are commonly latently or subclinically coin- load and an increase in CD4+ T cell count. HIV-seroposi- fected with HHV-8, the HHV-8-specific cytotoxic T cells tive subjects with IRIS episodes tend to be younger at the lodge in sites of HHV-8 subclinical infection, or in sites of time of introduction of HAART and tend to have a lower established KS lesions. In most of HIV-seropositive sub- median baseline CD4+ T cell percentage than HIV-serop- jects, these CD8+ T cells will be protective and will control ositive subjects who do not experience IRIS. Overall, the HHV-8 replication and spread, thus reducing the inci- median time to onset of IRIS in those subjects who display dence of new KS lesions, and at times bringing about this response is 12 weeks [92-96]. regression in established KS lesions. However in a minor- ity of HIV-seropositive subjects with subclinical HHV-8 HIV-seropositive subjects who are at greater risk for devel- infection, or with established KS, such an immune oping IRIS are those with low CD4+ T cell counts of < 100 response may be dysregulated and accompanied by an cells/ul [95,107], those with CD4+ T cell percentage of intensified HHV-8-specific inflammatory response para- <10%, and those of a younger age at the time of introduc- doxically causing a worsening of KS and as a consequence, tion of HAART [96]. There is no association between the the development of IRIS-KS [112]. risk for developing IRIS and the magnitude of the increase in CD4+ T cell count or the percentage of CD4+ T cell There could be other mechanisms that may be involved in increase, and the plasma load decrease following HAART the pathogenesis of IRIS-KS. As part of the immune resto- [95,96,108] In contrast, Shelburne et al.[94] and Breton et ration after HAART, there is a shift in the cytokine profile al.[109] found that HIV-IRIS is associated with a greater from the Th-2 to the Th-1 type. Th-1 cytokines have the increase in the percentage of CD4+ T cell one month after capacity to reactivate latent HHV-8 in blood and tissue the introduction of HAART and with a more pronounced cells, and as a consequence, HHV-8 can spread to unin- and persistent reduction in HIV load. Thus, there is some fected endothelial cells. Perhaps in a subset of HIV-serop- conflict in the immunological parameters associated with ositive subjects, the restored HHV-8-specific immune the development of HIV-IRIS. response following HAART is ineffective in controlling the increased HHV-8 antigens in blood and tissue cells, and as The definite association of the events of HIV-IRIS with a a result, paradoxically promotes the development of IRIS- low baseline CD4+ T cell percentage probably reflects a KS. higher burden of opportunistic subclinical pathogens at the time of HAART introduction. Such a high burden of Because of the inability of the immune response to con- antigenic stimulation together with a dysregulated trol the HHV-8 infection, two processes may occur in par- increased immune response during immunoreconstitu- allel; the development of an exaggerated tion after HAART, may be responsible for the develop- immunoinflammatory reaction characterized by the ment of HIV-IRIS [90]. increased production of inflammatory cytokines in order to combat HHV-8; and secondly, the increase in the HHV- The immunopathogenic mechanisms associated with IRIS 8 load in the tissues through autocrine and paracrine differ according to the type of pathogen involved [90]. mechanisms increase the production of inflammatory CD8+ cytotoxic T cell response is associated with IRIS cytokines, chemokines and growth factors. Together these induced by viral infections [110,111] and a delayed type- processes upregulate the expression of αvβ and α β , and 3 5 1 hypersensitivity or a lymphoproliferative reaction with MMPs that induce the IRIS-KS angioproliferation and IRIS induced by mycobacterial infections [90,112,113]. tumourigenesis [55]. In this context, HIV Tat protein and a profound state of immunosuppression do not signifi- IRIS associated HIV-KS cantly affect the development of IRIS-KS. Most HIV-seropositive subjects with KS do not demon- strate HHV-8-specific cytotoxic T lymphocyte response. Bower et al. [33], reported that 10 of 150 (6.6%) HAART- This lack of HHV-8-specific cellural immune response naïve HIV-seropositive subjects with KS either developed during HIV infection is a contributory factor in the devel- new KS lesions or exhibited rapid progression of existing Page 5 of 9 (page number not for citation purposes) Infectious Agents and Cancer 2008, 3:1 http://www.infectagentscancer.com/content/3/1/1 clinicopathologic study. Oral Surg Oral Med Oral Pathol Oral Radiol KS lesions within 2 months of starting HAART. These sub- and Endod 1997, 83:259-264. jects had a significantly higher CD4+ T cell count at the 9. Von Roenn JH: Clinical presentations and standard therapy of time of IRIS-KS diagnosis and a higher frequency of KS- AIDS-associated Kaposi's sarcoma. Hematol Oncol Clin North Am 2003, 17:747-762. associated oedema than HIV-seropositive subjects with KS 10. Monini P, Sgadari C, Barillari G, Ensoli B: HIV protease inhibitors: who did not develop IRIS. antiretroviral agents with anti-inflammatory, anti-ang- iogenic and anti-tumour activity. J Antimicrob Chemother 2003, 51:207-211. Summary 11. Hengge UR, Ruzicka T, Tyring SK, Stuschke M, Roggendorf M, The clinical course of HIV-KS is unpredictable. For some Schwartz RA, et al.: Update on Kaposi's sarcoma and other HHV8 associated diseases. Part 2: Pathogenesis, Castle- HIV-seropositive subjects, KS is a mild disease, while for man's disease and pleural effusion lymphoma. Lancet Infect Dis others it may be rapidly progressive and aggressive. 2002, 2:344-352. Regression of HIV-KS lesions and a substantial decrease in 12. Ensoli B, Sgadari C, Barillari G, Sirianni MC, Sturzl M, Monini P: Biol- ogy of Kaposi's sarcoma. Eur J Cancer 2001, 37:1251-69. the incidence of HIV-KS occur after the introduction of 13. Krown SE: Therapy of AIDS-associated Kaposi's sarcoma: tar- HAART. However, a small subset of HIV-seropositive sub- geting pathogenetic mechanisms. Hematol Oncol Clin North Am 2003, 17:763-783. jects with a low CD4 + T cell count at the time of HAART 14. Schwartz RA: Kaposi's sarcoma: An update. J Surg Oncol 2004, initiation, may develop IRIS associated HIV-KS shortly 87:146-151. thereafter. 15. Foreman KE, Friborg J, Chandran B, Katano H, Sata T, Mercader M, Nabel GJ, Nickoloff BJ: Injection of human herpesvirus-8 in human skin engrafted on SCID induces Kaposi's sarcoma- IRIS-KS is not a specific entity but it is a phenomenon like lesions. J Dermatol Sci 2001, 26:182-193. 16. Feller L, Lemmer J, Wood NH, Raubenheimer EJ: Necrotizing gin- which can be recognized by certain well defined circum- givitis of Kaposi sarcoma affected gingivae. SADJ 2006, stances: the presence of low CD4+ T cell counts at the time 61:314-317. of introduction of HAART; a temporal relationship 17. Moore PS, Chang Y: Detection of herpesvirus-like DNA sequences in Kaposi's sarcoma in patients with and without between rapid clinical progression of KS and the develop- HIV infection. N Eng J Med 1995, 332:1182-1185. ment of new KS lesions usually of about 8 weeks (though 18. Huang YQ, Li JJ, Kaplan MH, Poiesz B, Katabira E, Zhang WC, et al.: this period may range from 3 weeks to 22 weeks) after the Human herpesvirus-like nucleic acid in various forms of Kaposi's sarcoma. Lancet 1995, 345:759-761. initiation of HAART; and the suppression of HIV load and 19. Forman KE, Bacon PE, Hsi ED, Nickoloff BJ: In situ polymerase restoration of CD4+ T cell count. chain reaction-based localization studies support role of human herpes virus-8 as the cause of two AIDS-related neo- plasms: Kaposi's sarcoma and body cavity lymphoma. J Clin Competing interests Invest 1997, 99:2971-2978. The author(s) declare that they have no competing inter- 20. Whitby D, Howard MR, Tenant-Flowers M, Brink NS, Copas A, Boshoff C, et al.: Detection of Kaposi sarcoma associated her- ests. pesvirus in peripheral blood of HIV-infected individuals and progression of Kaposi sarcoma. Lancet 1995, 346:799-802. 21. Moore PS, Kingsley LA, Holmberg SD, Spira T, Gupta P, Hoover DR, References et al.: Kaposi's sarcoma-associated herpesvirus infection prior 1. Leao JC, Caterino-de-Araujo A, Porter SR, Scully C: Human her- to onset of Kaposi's sarcoma. AIDS 1996, 10:175-180. pesvirus 8 (HHV-8) and the etiopathogenesis of Kaposi's sar- 22. Cattelan A, Calabro ML, Gasperini P, Aversa SM, Zanchetta M, coma. Rev Hosp Clin Fac Med Sao Paulo 2002, 57:175-186. Meneghetti F, et al.: Acquired immunodeficiency syndrome- 2. Tappero JW, Conant MA, Wolfe SF, Berger TG: Kaposi's sarcoma. related Kaposi's sarcoma regression after highly active Epidemiology, pathogenesis, histology, clinical spectrum, antiretroviral therapy: biologic correlates of clinical out- staging criteria and therapy. J Am Acad Dermatol 1993, come. J Natl Cancer Inst Monogr 2001, 27:44-49. 28:371-395. 23. Bubman D, Cesarman E: Pathogenesis of Kaposi's sarcoma. 3. Jensen KK, Manfra DJ, Grisotto MG, Martin AP, Vassileva G, Kelly K, Hematol Oncol Clin North Am 2003, 17:717-745. et al.: The human herpes virus 8-encoded chemokine recep- 24. Engels EA, Biggar RJ, Marshall VA, Walters MA, Gamade CJ, Whitby tor is required for angioproliferation in a murine model of D, et al.: Detection and quantification of Kaposi's sarcoma Kaposi's sarcoma. J Immunol 2005, 174:3686-3694. associated herpes virus to predict AIDS-associated Kaposi's 4. Feller L, Jadwat Y, Raubenheimer EJ: Kaposi sarcoma and calcium sarcoma. AIDS 2003, 17:1847-1851. channel blocker-induced gingival enlargement occurring 25. Simpson GR, Schultz TF, Whitby D, Cook PM, Boshoff C, Rainbow L, simultaneously: Review of the literature and report of a case. et al.: Prevalence of Kaposi's sarcoma associated herpesvirus Oral Biosci Med 2004, 4:291-297. infection measured by antibodies to recombinant caspid 5. Gallafent JH, Buskin SE, De Turk PB, Aboulafia DM: Profile of protein and latent immunofluorescence antigen. Lancet 1996, patients with Kaposi's Sarcoma in the era of highly active 348:1133-1138. antiretroviral therapy. J Clin Oncol 2005, 23:1253-1260. 26. Gao SJ, Kingsley L, Hoover DR, Spiro TJ, Rinaldo CR, Saah A, et al.: 6. Fauci AS, Lane HC: Human immunodeficiency virus disease: Seroconversion to antibodies against Kaposi's sarcoma-asso- Aids and related disorders. In Harrison's Principles of Internal Med- ciated herpesvirus-related latent nuclear antigens before the icine 16th edition. Edited by: Kasper DL, Braunwald E, Fauci AS, development of Kaposi's sarcoma. N Engl J Med 1996, Hauser SL, Longo DL, Jameson JL. New York: McGraw-Hill; 335:233-241. 2005:1076-1139. 27. Verbeek W, Frankel M, Miles S, et al.: Seroprevalence of HHV-8 7. Hengge UR, Ruzicka T, Tyring SK, Stuschke M, Roggendorf M, antibodies in HIV-positive homosexual men without Schwartz RA, et al.: Update on Kaposi's sarcoma and other Kaposi's sarcoma and their clinical follow-up. Am J Clin Pathol HHV8 associated diseases. Part 1: Epidemiology, environ- 1998, 109:778-783. mental predispositions, clinical manifestations and therapy. 28. Mendez JC, Procop GW, Espy MJ, Paya CV, Smith TF: Detection Lancet Infect Dis 2002, 2:281-292. and semiquantitative analysis of human herpesvirus 8 DNA 8. Flaitz CM, Jin YT, Hicks MJ, Nichols CM, Wang YW, Su IJ: Kaposi's in specimens from patients with Kaposi's sarcoma. J Clin sarcoma associated herpesvirus-like DNA sequences Microbiol 1998, 36:2220-2222. (KSHV/HHV-8) in oral AIDS-Kaposi's sarcoma: a PCR and Page 6 of 9 (page number not for citation purposes) Infectious Agents and Cancer 2008, 3:1 http://www.infectagentscancer.com/content/3/1/1 29. Iscovich J, Boffetta P, Franceschi S, Azizi E, Sarid R: Classic Kaposi active antiretroviral therapy. J Invest Dermatol 2001, sarcoma: Epidemiology and risk factors. Cancer 2000, 117:858-863. 88:500-517. 48. Leitch H, Trudeau M, Routy JP: Effect of protease inhibitor-based 30. Connick E, Kane MA, White IE, Ryder J, Campbell TB: Immune highly active antiretroviral therapy on survival in HIV-associ- reconstitution inflammatory syndrome associated with ated advanced Kaposi's sarcoma patients treated with Kaposi sarcoma during potent antiretroviral therapy. Clin chemotherapy. HIV Clin Trials 2003, 4:107-114. Infect Dis 2004, 39:1852-1855. 49. Bower M, Fox P, Fife K, Gill J, Nelson M, Gazzard B, et al.: Highly 31. Ensoli B, Barillari G, Salahuddin SZ, Gallo RC, Wong-Staal F: Tat pro- active anti-retroviral therapy (HAART) prolongs time to tein of HIV-1 stimulates growth of cells derived from treatment failure in Kaposi's sarcoma. AIDS 1999, Kaposi's sarcoma lesions of AIDS patients. Nature 1990, 13:2105-2111. 345:84-86. 50. Martinelli C, Zazzi M, Ambu S, Bartolozzi D, Corsi P, Leoncini F: 32. Ensoli B, Gendelman R, Markham P, Fiorelli V, Columbini S, Raffeld M, Complete regression of AIDS-related Kaposi's sarcoma- et al.: Synergy between basic fibroblast growth factor and the associated human herpesvirus-8 during therapy with indina- HIV-1 Tat protein in induction of Kaposi's sarcoma. Nature vir. AIDS 1998, 12:1717-1719. 1994, 371:674-680. 51. Paparizos VA, Kyriakis KP, Papastamopoulos V, Hadjivassiliou M, Sta- 33. Bower M, Nelson M, Young AM, Thirlwell C, Newsom-Davis T, Man- vrinaes NG: Response of AIDS-associated Kaposi sarcoma to dalia S, et al.: Immune reconstitution inflammatory syndrome highly active antiretroviral therapy alone. J Acquir Immune Defic associated with Kaposi's sarcoma. J Clin Oncol 2005, Syndr 2002, 30:257-258. 23:5224-5228. 52. Winceslaus J: Regression of AIDS-related pleural effusion with 34. Palellla FJ Jr, Delaney KM, Marman AC, Loveless MO, Fuhreh J, Salten HAART: highly active antiretroviral therapy. Int J STD AIDS GA, et al.: Declining morbidity and mortality among patients 1998, 9:368-370. with advanced human immunodeficiency virus infection. 53. Boshoff C, Weiss R: AIDS-related malignancies. Nat Rev Cancer HIV Outpatient Study Investigators. N Engl J Med 2003, 2002, 2:373-382. 338:853-860. 54. Nasti G, Martellotta F, Beretta M, Menna M, Fasan M, Di Perri G, et 35. Portsmouth S, Stebbing J, Gazzard B: Current treatment of HIV al.: Impact of highly active antiretroviral therapy on the pre- infection. Curr Top Med Chem 2003, 3:1458-1466. senting features and outcome of patients with acquired 36. Autran B, Carcelain G, Li TS, Blanc C, Mathez D, Tubiana R, et al.: immunodeficiency syndrome-related Kaposi's sarcoma. Can- Positive effects of combined antiretroviral therapy on CD4+ cer 2003, 98:2440-2446. T cell homeostasis and function in advanced HIV disease. Sci- 55. Leidner RS, Aboulafia DM: Recrudescent Kaposi's sarcoma after ence 1997, 277:112-116. initiation of HAART: A manifestation of immune reconstitu- 37. Quinlivan EB, Zhang C, Stewart PW, Komoltri C, Davis MG, Wehbie tion syndrome. Aids patient care STD 2005, 19:635-644. RS: Elevated virus loads of Kaposi's sarcoma-associated 56. Shelburne SA 3rd, Hamill RJ, Rodriguez-Barradas MC, Greenberg SB, human herpesvirus 8 predict Kaposi's sarcoma disease pro- Atmor RL, Musher DW, et al.: Immune reconstitution inflamma- gression, but elevated levels of human immunodeficiency tory syndrome: emergence of a unique syndrome during virus type 1 do not. J Infect Dis 2002, 185:1736-1744. highly active antiretroviral therapy. Medicine 2002, 81:213-227. 38. Jones JL, Hanson DL, Dworkin MS, Jaffe HW, et al.: Incidence and 57. Weir A, Wansbrough-Jones M: Mucosal Kaposi's sarcoma fol- trends in Kaposi's sarcoma in the era of effective antiretrovi- lowing protease inhibitor therapy in an HIV-infected patient. ral therapy. J Acquir Immune Defic Syndr 2000, 24:270-274. AIDS 1997, 11:1895-1896. 39. Hermans P, Lundgren J, Sommereijns B, Katlama C, Chiesi A, Goebel 58. Rizos E, Drosos AA, Ioannidis JP: Isolated intraparotid Kaposi FD, et al.: Survival of European patients with Kaposi's sarcoma sarcoma in human immunodeficiency virus type 1 infection. as AIDS-defining condition during the first decade of AIDS. Mayo Clin Proc 2003, 78:1561-1563. AIDS in Europe study group. AIDS 1997, 11:525-531. 59. Crane HM, Deubner H, Huang JC, Swanson PE, Harrington RD: Fatal 40. Portsmouth S, Stebbing J, Gill J, Mandalia S, Bower M, Nelson M, et al.: Kaposi's sarcoma-associated immune reconstitution follow- A comparison of regimens based on non-nucleoside reverse ing HAART initiation. Int J STD AIDS 2005, 16:80-83. transcriptase inhibitors or protease inhibitors in preventing 60. Mallery SR, Pei P, Kang J, Zhu G, Ness GM, Schwendeman SP: Sus- Kaposi's sarcoma. AIDS 2003, 17:F17-22. tained antiogenesis enable in vivo transplantation of muco- 41. Jacobson LP, Yamashita TE, Detels R, Margolick JB, Chmiel JS, Kings- cutaneous derived AIDS-related Kaposi's sarcoma cells in ley LA, et al.: Impact of potent antiretroviral therapy on the murine hosts. Carcinogenesis 2000, 21:1647-1653. incidence of Kaposi's sarcoma and non-Hodgkin's lympho- 61. Barillari G, Ensoli B: Angiogenic effects of extracellular human mas among HIV-1-infected individuals. J Acquir Immun Defic immunodeficiency virus type 1 Tat protein and its role in the Syndr 1999, 21:S34-41. pathogenesis of AIDS-associated Kaposi's sarcoma. Clin 42. International Collaboration on HIV and Cancer: Highly active Microbiol Rev 2002, 15:310-326. antiretroviral therapy and incidence of cancer in human 62. Sodhi A, Montaner S, Gutkind JS: Does dysregulated expression immunodeficiency virus-infected adults. J Natl Cancer Institute of a deregulated viral GPCR trigger Kaposi's sarcomagene- 2000, 92:1823-1830. sis? FASEB J 2004, 18:422-427. 43. Lebbe C, Blum L, Pellet C, Blanchard G, Verola O, Morel P, et al.: 63. Sodhi A, Montaner S, Patel V, Gomez-Roman JJ, Li Y, Sausville EA, et Clinical and biological impact of antiretroviral therapy with al.: Akt plays a central role in sarcomagenesis induced by protease inhibitors on HIV-related Kaposi's sarcoma. AIDS Kaposi's sarcoma herpesvirus-encoded G protein-coupled 1998, 12:F45-49. receptor. Proc Natl Acad Sci USA 2004, 101:4821-4826. 44. Cattelan AM, Calabro ML, Aversa SM, Zanchetta M, Meneghetti F, De 64. Sodhi A, Montaner S, Patel V, Zohar M, Bais C, Mesri EA, et al.: The Rossi A, et al.: Regression of AIDS-related Kaposi's sarcoma Kaposi's sarcoma-associated herpes virus G protein-coupled following antiretroviral therapy with protease inhibitors: receptor up-regulates vascular endothelial growth factor biological correlates of clinical outcome. Eur J Cancer 1999, expression and secretion through mitogen-activated protein 35:1809-1815. kinase and p38 pathways acting on hypoxia-inducible factor 45. Aboulafia DM: The epidemiologic, pathologic, and clinical fea- 1 alpha. Cancer Res 2000, 60:4873-4880. tures of AIDS-associated pulmonary Kaposi's sarcoma. Chest 65. Naranatt PP, Krishnan HH, Svojanovsky SR, Bloomer C, Mathur S, 2000, 117:1128-1145. Chandran B: Host gene induction and transcriptional repro- 46. Holkova B, Takeshita K, Cheng DM, Volm M, Wasserheit C, Demo- gramming in Kaposi's sarcoma-associated herpesvirus poulos R, et al.: Effect of highly active antiretroviral therapy on (KSHV/HHV-8)-infected endothelial, fibroblast, and B cells: survival in patients with AIDS-associated pulmonary insights into modulation events early during infection. Cancer Kaposi's sarcoma treated with chemotherapy. J Clin Oncol Res 2004, 64:72-84. 2001, 19:3848-3851. 66. Ensoli B, Sturzl M, Monini P: Reactivation and role of HHV-8 in 47. Pellet C, Chevret S, Blum L, Gauville C, Hurault M, Blanchard G, et al.: Kaposi's sarcoma initiation. Adv Cancer Res 2001, 81:161-200. Virologic and immunologic parameters that predict clinical 67. Buttiglieri S, Deregibus MC, Bravo S, Cassoni P, Chiarle R, Bussolati response of AIDS-associated Kaposi's sarcoma to highly B, et al.: Role of Pax 2 in apoptosis resistance and proinvasive Page 7 of 9 (page number not for citation purposes) Infectious Agents and Cancer 2008, 3:1 http://www.infectagentscancer.com/content/3/1/1 phenotype of Kaposi's sarcoma cells. J Biol Chem 2004, expression of αvβ3 and α5β1 integrins during human 279:4136-4143. melanoma cell invasion. Cancer Res 1993, 53:3411-3415. 68. Schwartz M, Murphy PM: Kaposi's sarcoma-associated herpesvi- 86. Wink DA, Vodovotz Y, Laval J, Laval F, Dewhirst MW, Mitchell JB: rus G protein-coupled receptor constitutively activates NF- The multifaceted roles of nitric oxide in cancer. Carcinogenesis B and induces proinflammatory cytokine and chemokine 1998, 19:711-721. production via a c-terminal signaling determinant. J Immunol 87. Lucey DR, Clerici M, Shearer GM: Type 1 and Type 2 cytokine 2001, 167:505-513. dysregulation in human infectious, neoplastic and inflamma- 69. Rabkin CS, Janz S, Lash A, Coleman AE, Musaba E, Liotta L, et al.: tory diseases. Clin Microbiol Rev 1996, 9:532-562. Monoclonal origin of muilticentric Kaposi's sarcoma lesions. 88. Wilkinson J, Cope A, Gill J, Bourboulia D, Hayes P, Imami N, et al.: N Engl J Med 1997, 336:988-993. Identification of Kaposi's sarcoma-associated herpesvirus 70. Gill PS, Tsai YC, Rao AP, Spruck CH 3rd, Zheng T, Harrington WA (KSHV)-specific responses in human immunodeficiency Jr, et al.: Evidence for multiclonality in multicentric Kaposi's virus type 1-Infected patients receiving highly active antiret- sarcoma. Proc Natl Acad Sci USA 1998, 95:8257-8261. roviral therapy. J Virol 2002, 76:2634-2640. 71. Mallery SR, Pei P, Landwehr DJ, Clark CM, Bradburn JE, Ness GM, et 89. Robertson P, Scadden DT: Immune reconstitution in HIV infec- al.: Implications for oxidative and nitrative stress in the tion and its relationship to cancer. Hematol Oncol Clin North Am pathogenesis of AIDS-related Kaposi's sarcoma. Carcinogene- 2003, 17:703-716. sis 2004, 25:597-603. 90. Cheng VCC, Yuen KY, Chan WM, Wong SSY, Ma ESK, Chan RMT: 72. Hynes RO: Integrins: versatility, modulation and signaling in Immunorestitution disease involving the innate and adaptive cell adhesion. Cell 1992, 69:11-25. response. Clin Infec Dis 2000, 30:882-892. 73. Barillari G, Albonici L, Incerpi S, Bogetto L, Pistritto G, Volpi A, et al.: 91. Jubault V, Penfornis A, Schillo F, Hoen B, Izembart M, Timsit J, et al.: Inflammatory cytokines stimulate vascular smooth muscle Sequential occurrence of thyroid autoantibodies and Grave's cells locomotion and growth by enhancing α5β1 integrin disease after immune restoration in severely immunocom- expression and function. Atherosclerosis 2001, 154:377-385. promised human immunodeficiency virus-1 infected 74. Toschi E, Barillari G, Sgadari C, Bacigalupo I, Ceresto A, Carlei D, et patients. J Clin Endocrinal Metab 2000, 85:4254-4257. al.: Activation of matrix-metalloproteinase-2 and mem- 92. Lawn SD, Bekker LG, Miller RF: Immune reconstitution disease brane-type-1-matrix-metalloproteinase in endothelial cells associated with mycobacterial infections in HIV-infected and induction of vascular permeability in vivo by human individuals receiving antiretrovirals. Lancet Infect Dis 2005, immunodeficiency virus-1 Tat protein and basic fibroblast 5:361-373. growth factor. Mol Biol Cell 2001, 12:2934-2946. 93. Shelburne SA 3rd, Hamill RJ: The immune reconstitution inflam- 75. Barillari G, Sgadari C, Fiorelli V, Samaniego F, Colombini S, Manzari V, matory syndrome. AIDS Rev 2003, 5:67-79. et al.: The Tat protein of human immunodeficiency virus 94. Shelburne SA, Visnegarwala F, Darcourt J, Gravis EA, Giordano TP, type-1 promotes vascular cell growth and locomotion by White AC: Incidence and risk factors for immune reconstitu- engaging the α5β1 and αvβ3 integrins and by mobilizing tion inflammatory syndrome during highly active antiretro- sequestered basic fibroblast growth factor. Blood 1999, viral therapy. AIDS 2005, 19:399-406. 94:663-672. 95. French MA, Lenzo N, John M, Mallai SA, McKinnin EJ, James IR, et al.: 76. Toschi E, Bacigalupo I, Strippoli R, Chiozzini C, Cereseto A, Falchi M, Immune restoration disease after the treatment of immun- et al.: HIV-1 Tat regulates endothelial cell cycle progression odeficient HIV-infected patients with highly active antiretro- via activation of the Ras/ERK MAPK signaling pathways. Mol viral therapy. HIV Med 2000, 1:107-115. Biol Cell 2006, 17:1985-1994. 96. Ratnam I, Chiu C, Kandala NB, Easterbrook PJ: Incidence and risk 77. Fanales Belasio E, Moretti S, Nappi F, Barillari G, Micheletti F, Cafaro factors for immune reconstitution inflammatory syndrome A, et al.: Native HIV-Tat protein targerts monocyte-derived in an ethnically diverse HIV type-1-infected cohorot. Clin dendritic cells and enhances their maturation, function, and Infect Dis 2006, 42:418-427. antigen-specific T cell responses. J Immunol 2002, 168:197-206. 97. Valdez H, Connick E, Smith KY, Leerman MM, Bosch RJ, Kim RS, et 78. Lamoreaux WJ, Fitzgerald ME, Reiner A, Hasty KA, Charles ST: Vas- al.: Limited immune restoration after 3 years' suppression of cular endothelial growth factor increases release of gelati- HIV-1 replication in patients with moderately advanced dis- nase A and decrease release of tissue inhibitor of ease. AIDS 2002, 16:1859-1866. metalloproteinases by microvascular endothelial cells in 98. Douek DC, McFarland RD, Keiser PH, Cage FA, Massey JM, Haynes vitro. Microvasc Res 1998, 55:29-42. BF, et al.: Changes in thymic function with age and during 79. Blotnick S, Peoples GE, Freeman MR, Eberlein TJ, Klagsbrun M: T- treatment of HIV infection. Nature 1998, 396:690-695. lymphocytes synthesize and export heparin-binding epider- 99. Zhang I, Lewin SR, Markowitz M, Linn HH, Skulski E, Karanicolas R, et mal growth factor-like growth factor, and basic fibroblast al.: Measuring recent thymic emigrants in blood of normal growth factor, mitogens for vascular cells and fibroblasts: dif- and HIV-1-infected individuals before and after effective ferential production and release by CD4+ and CD8+ T cells. therapy. J Exp Med 1999, 190:725-732. Proc Natl Acad Saci USA 1994, 91:2890-2894. 100. Carcelain G, Debre P, Autran B: Reconstitution of CD4+ T lym- 80. Barillari G, Sgadari C, Palladino C, Gendelman R, Caputo A, Morris phocytes in HIV-infected individuals following antiretroviral CB, et al.: Inflammatory cytokines synergize with HIV-1 Tat therapy. Curr Opin Immunol 2001, 13:483-488. protein to promote angiogenesis and Kaposi's sarcoma via 101. Carcelain G, Tubiana R, Samri A, Calvez V, Delaugerre C, Augut H, et induction of basic fibroblast growth factor and αvβ3 integrin. al.: Transient mobilization of human immunodeficiency virus J Immunol 1999, 15:1929-1935. (HIV) – specific CD4 T-helper cells fails to control virus 81. Samaniego F, Markham PD, Gallo RC, Ensoli B: Inflammatory rebounds during intermittent antiretroviral therapy in cytokines induce AIDS-Kaposi's sarcoma-derived spindle chronic HIV type 1 infection. J Virol 2001, 75:234-241. cells to produce and release basic fibroblast growth factor 102. Pakker NG, Notermans DW, be Boer RJ, Roos MT, de Wolf F, Hill and enhance Kaposi's sarcoma-like lesion formation in nude A, et al.: Biphasic kinetics of peripheral blood T cells after tri- mice. J Immunol 1995, 154:3582-3592. ple combination therapy in HIV-1 infection: a composite of 82. Bussolino F, Mitola S, Serini G, Barillari G, Ensoli B: Interactions redistribution and proliferation. Nat Med 1998, 4:208-214. between endothelial cells and HIV-1. Int J Biochem Cell Biol 2001, 103. Bucy RP, Hockett RD, Derdeyn CA, Saag MS, Squires K, Sillers M, et 33:371-390. al.: Initial increase in blood CD4(+) lymphocytes after HIV 83. Ferrari N, Morini M, Pfeffer U, Minghelli S, Noonan DM, Albini A: antiretroviral therapy reflects redistribution from lymphoid Inhibition of Kaposi's sarcoma in vivo by fenretinide. Clin Can- tissues. J Clin Invest 1999, 103:1391-1398. cer Res 2003, 9:6020-6029. 104. Connick E, Lederman MM, Kotzin BL, Spritzler J, Kuritzkes DR, St 84. Brooks PC, Stromblad S, Sanders LC, von Schalscha TL, Aimes RT, Clair M, et al.: Immune reconstitution in the first year of Stetler-Stevenson WG, et al.: Localization of matrix metallopro- potent antiretroviral therapy and its relationship to virologic teinase MMP-2 to the surface of invasive cells by interaction response. J Infec Dis 2000, 181:358-363. with integrin αvβ3. Cell 1996, 85:683-693. 105. Lederman MM, Connick E, Landay A, Kuritzkes DR, Spritzler J, St 85. Seftor RE, Seftor EA, Stetler-Stevenson WG, Welch DR, Hendrix MJ: Clair M, et al.: Immunologic responses associated with 12 The 72 kDa type IV collagenase is modulated via differential weeks combination antiretroviral therapy consisting of zido- Page 8 of 9 (page number not for citation purposes) Infectious Agents and Cancer 2008, 3:1 http://www.infectagentscancer.com/content/3/1/1 vudine, lamivudine and ritonavir: results of AIDS Clinical Trials Group Protocol 315. J Infect Dis 1998, 178:70-79. 106. Lederman MM: Immune restoration and CD4+ T-cell function with antiretroviral therapies. AIDS 2001, 15(Suppl 2):S11-15. 107. Jevtovic DJ, Salemovic D, Pesic I, Zerjav S, Djurkovic-Djakovic O: The prevalence and risk of immune restoration disease in HIV-infected patients treated with highly active antiretrovi- ral therapy. HIV Med 2005, 6:140-143. 108. Robertson J, Meier M, Wall J, Ying J, Fichtenbaum CJ: Immune reconstitution syndrome in HIV: Validating a case definition and identifying clinical predictors in persons initiating antiretroviral therapy. Clin Infect Dis 2006, 42:1639-1646. 109. Breton G, Duval X, Estellat C, Paoletti X, Bonnet D, Mvondo D, et al.: Determinants of immune reconstitution inflammatory syn- drome in HIV type-1-infected patients with tuberculosis after initiation of antiretroviral therapy. Clin Infect Dis 2004, 39:1709-1712. 110. Martinez E, Gatell J, Moran Y, Aznar E, Buira E, Guelar A, et al.: High incidence of herpes zoster in patients with AIDS soon after therapy with protease inhibitors. Clin Infect Dis 1998, 27:1510-1513. 111. Domingo P, Torres OH, Ris J, Vazquez G: Herpes zoster as an immune reconstitution disease after initiation of combina- tion antiretroviral therapy in patients with human immuno- deficiency virus type-1 infection. Am J Med 2001, 110:605-609. 112. Foudraine NA, Hovenkamp E, Natermans DW, Meenhorst PL, Klein MR, Lange JMA, et al.: Immunopathology as a result of highly active antiretroviral therapy in HIV-1-infeted patients. AIDS 1999, 13:177-184. 113. French MAH, Malal SA, Dawkins RL: Zidovudine-induced restora- tion of cell-mediated immunity to mycobacteria in immuno- deficient HIV-infected patients. AIDS 1992, 6:1293-1297. 114. Osman M, Kubo T, Gill J, Neipel F, Becker M, Smith G, et al.: Identi- fication of human herpesvirus 8-specific cytotoxic T-cell responses. J Virol 1999, 73:6136-6140. 115. Hirsh H, Kaufmann G, Sendi P, Battegay M: Immune reconstitu- tion in HIV-infected patients. Clin Infect Dis 2004, 38:1159-1166. Publish with Bio Med Central and every scientist can read your work free of charge "BioMed Central will be the most significant development for disseminating the results of biomedical researc h in our lifetime." 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Insights into pathogenic events of HIV-associated Kaposi sarcoma and immune reconstitution syndrome related Kaposi sarcoma

Feller, Liviu; Lemmer, Johan
Infectious Agents and Cancer , Volume 3 (1) – Jan 21, 2008
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Biomedicine; Cancer Research; Infectious Diseases; Oncology
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Abstract

A decrease in the incidence of human immune deficiency virus-associated Kaposi sarcoma (HIV- KS) and regression of some established HIV-KS lesions is evident after the introduction of highly active anti-retroviral treatment (HAART), and is attributed to generalized immune restoration, to the reconstitution of human herpesvirus (HHV)-8 specific cellular immune responses, and to the decrease in HIV Tat protein and HHV-8 loads following HAART. However, a small subset of HIV- seropositive subjects with a low CD4+ T cell count at the time of introduction of HAART, may develop HIV-KS as immune reconstitution inflammatory syndrome (IRIS) within 8 weeks thereafter. commonly by proximal lymph node involvement [9]. The Introduction Kaposi sarcoma (KS) is the most common human immu- pathogenesis of HIV-KS is complex, and involves interac- nodeficiency virus (HIV)-associated neoplasm [1]. HIV- tion between human herpesvirus (HHV)-8, HIV, inflam- associated Kaposi sarcoma (HIV-KS) lesions are character- matory cytokines, and angiogenic factors in the presence ized microscopically by angiogenesis, the presence of of profound immune suppression [10-12]. However, the spindle-shaped tumour cells, inflammatory cell infiltrates understanding of how these multiple factors interplay to dominated by mononuclear cells, extravasated erythro- initiate KS is incomplete [3]. cytes and oedema [2-4]. Clinically, HIV-seropositive sub- jects with KS exhibit mainly multifocal mucocutaneous HHV-8 is present in all four epidemiological forms of KS patches, plaques and nodules, and less frequently organ (classic, endemic, iatrogenic and HIV-KS). Seroprevalence involvement [5-7]. The most common site of extra-muco- studies demonstrate that HHV-8 DNA in peripheral blood cutaneous HIV-KS involvement is the lymph nodes fol- mononuclear cells (PBMC) and specific antibodies to lowed by the gastro-intestinal tract and the lungs. The oral HHV-8 are associated with increased risk of KS, and there cavity is commonly affected and is the initial site of is a positive correlation between the HHV-8 viral load and involvement with KS in about 20% of HIV-seropositive the severity of KS. These lines of evidence indicate that subjects with KS [8]. Oedema is a major clinical feature HHV-8 is necessary for the development of KS, but since associated with advanced KS. It results most frequently HHV-8 seroconversion in the general population is not when a local inflammatory reaction induced by produc- uncommon and is much more common in HIV-seroposi- tion of cytokines by KS cells is complicated either by lym- tive subjects, but yet only some members of these popula- phatic obstruction by the enlarging tumour itself, or less Page 1 of 9 (page number not for citation purposes) Infectious Agents and Cancer 2008, 3:1 http://www.infectagentscancer.com/content/3/1/1 tions develop KS, other co-factors are clearly necessary for become nodular and may have an aggressive clinical the development of KS [13-29]. behaviour [60,61]. HIV contributes to the pathogenesis of KS through several The late-stage maculo-papular HIV-KS lesions are charac- mechanisms: HIV Tat protein directly promotes HHV-8 terized by proliferation of spindle cells, of lymphatic and/ replication [30,31]; HIV induces the production of or blood vascular endothelial origin. The spindle cells inflammatory cytokines [12,32], and causes a profound become the predominant cell type, though the vascular immune impairment that is conducive to the develop- element is always evident [23,65,66]. The progression of ment of KS. The incidence and aggressiveness of KS is sub- HIV-KS is attributed to dysregulation in cell cycle growth stantially increased in HIV-seropositive subjects and resistance to apoptotic signals mediated by altered compared to HIV-seronegative subjects [10,31,32]. This cytokine networks, latent and dysregulated lytic HHV-8 emphasizes the important role of HIV in the natural genes and HIV Tat protein [3,67]. course of HIV-KS. Early-stage HIV-KS is a polyclonal reactive angioprolifera- The use of highly active antiretroviral therapy (HAART) tive disorder. This is evident from the multifocal charac- has resulted in a dramatic reduction in the morbidity and teristic of the HIV-KS lesions in the absence of metastasis; mortality in HIV-seropositive subjects [33-36]. HAART, by the occasional regression of HIV-KS lesions either although not directly affecting HHV-8 replication, indi- spontaneously or following the introduction of HAART; rectly brings about a decrease in HHV-8 viral load [37], a and by the lack of clonality [68]. In contrast, late stage substantial reduction in the prevalence and incidence of HIV-KS lesions from disparate subjects may show a spec- HIV-KS [38-42], and improvement in the clinical manifes- trum of multiclonal origin, monoclonality, oligoclonality tation of KS [43-52]. and polyclonality, and it is likely that a subset of late-stage lesional cells of monoclonal origin undergo malignant However, HAART does not ensure that KS will not transformation [69,70]. develop, and in subjects receiving HAART, KS remains the most frequent HIV-associated neoplasm [5,53]. HIV-sero- Most of HIV-KS spindle cells express HHV-8 latent genes, positive subjects who had already received HAART at the but not genes that are involved in lytic reactivation and time of KS diagnosis, usually have less aggressive KS dis- replication of latently infected cells. However, some of the ease compared to HIV-seropositive subjects who were virally infected KS cells express HHV-8 lytic genes, that HAART naïve at the time of KS diagnosis [5,54]. In addi- provide paracrine angioproliferative inductive signals to tion, KS sometimes recrudesces as an immune reconstitu- neighbouring endothelial and spindle cells mediating tion inflammatory syndrome (IRIS) in HIV-seropositive angiogenesis and spindle cell proliferation [23]. subjects shortly after the introduction of HAART, despite an improvement in the CD4+ T cell count and controlled The persistent endothelial and spindle cell proliferation, HIV viremia [55-60]. in response to HHV-8 induced inflammatory and growth factors, and to HHV-8 oncogenes leads to dysregulated cell proliferation and survival, followed by cellular trans- The natural course of HIV-KS There is a compelling body of information that supports formation and eventual progression to a monoclonal the concept that HIV-KS is an opportunistic tumour that tumour [12,13,23]. The malignant transformation of HIV- starts as a reactive hyperplasia and eventually may KS cells, when and if it occurs, is probably driven by HHV- progress to a true neoplasia [12,13,16,23,60-64]. 8 latent oncogenes and by the dysregulated constitutive activity of viral G protein-coupled receptor (vGPCR) HIV-KS has its origin in an environment induced by expressed outside the lytic phase of the virus replication inflammatory T helper (Th)-1 cytokines associated with a cycle, without notable cellular genetic and epigenetic marked impairment of cellular immune responses, mutation of cell cycle genes and/or tumour suppressor brought about by HIV infection. The inflammatory infil- genes [3,62]. trate in HIV-KS lesions comprise CD8+ T cells, monocytes, macrophages and dendritic cells. These cells produce The implication of inflammatory cytokines in the inflammatory cytokines that together with HHV-8 gene pathogenesis of HIV-KS products, activate endothelial cells and trigger the devel- The pathogenesis of HIV-KS is related to infection with opment of HIV-KS. Early HIV-KS lesions manifest clini- HHV-8 and HIV, and to persistent inflammation in the cally as indolent red-purple macules or papules, that show presence of high level of Th1-type inflammatory cytokines proliferation of endothelial cells and formation of slit- including tumour necrosis factor (TNF)-α, interferon shaped vascular channels resembling well vascularized (INF)-γ, interleukin (IL)-1β, and IL-6, within an environ- exuberant granulation tissue. In time, HIV-KS lesions ment of immunosuppression. Increased HIV and HHV-8 Page 2 of 9 (page number not for citation purposes) Infectious Agents and Cancer 2008, 3:1 http://www.infectagentscancer.com/content/3/1/1 loads and concurrent opportunistic infections only serve greater aggressiveness in clinical behaviour of HIV-KS to perpetuate the inflammatory state [60,71]. It is proba- compared to other epidemiological forms of KS. ble that the increased level of inflammatory and ang- iogenic cytokines in all epidemiological forms of KS is the The role of bFGF and VEGF in the pathogenesis consequence of the local host immune activation against of HIV-KS HHV-8 and the HHV-8 release of cytokines in response to VEGF and bFGF are angiogenic growth factors that are the output of the HHV-8 genes [11,13]. powerfully expressed in HIV-KS lesions and promote ang- iogenesis. Both induce MMPs production by endothelial High levels of inflammatory cytokines in early KS lesions cells, and vascular permeability and subsequently oedema trigger endothelial cells to express activation markers that is an important feature of HIV-KS [74,78]. bFGF is including vascular cell adhesion molecules, matrix metal- produced by immunoregulatory cells, that are present in loproteinase (MMP), α β and αVβ integrins, growth fac- HIV-KS lesions, and by activated endothelial cells [79,80]. 5 1 3 tors such as vascular endothelial growth factor (VEGF) bFGF has an instrumental role in the development of HIV- and basic fibroblast growth factor (bFGF), and inflamma- KS. It can initiate and sustain neovascularization by pro- tory and angiogenic cytokines acting in both paracrine viding mitogenic signals to activated endothelial cells and and autocrine manner. These activated endothelial cells spindle cells [32,60,81]. This concept is supported by acquire abnormal phenotypic and functional features reports that the expression of bFGF is upregulated in HIV- (angiogenic phenotype) that may initiate and promote KS spindle cells, and antibodies to bFGF mRNA substan- the development of HIV-KS [61]. tially reduce the angiogenic and proliferative potential of HIV-KS cells [71]. In HIV-seropositive subjects with KS, Inflammatory cytokines have the capacity to reactivate bFGF mediates Tat-induced endothelial cell proliferation, latent HHV-8, resulting in an increase of HHV-8 plasma and acts with HIV Tat in promoting the production of load and spread of HHV-8 in tissues, and to promote HIV MMPs by endothelial cells[72,82]. replication, leading to a further production of HIV Tat protein and deterioration in host immune responses. VEGF is a potent specific endothelial cell mitogen pro- Thus, inflammatory cytokines have the potential to per- duced by HIV-KS endothelial and spindle cells in response petuate an environment conducive to HIV-KS initiation to inflammatory cytokines that induce angiogenesis and progression [61]. through autocrine mechanisms [23,83]. VEGF can syner- gise with bFGF to induce vascular permeability and α β and αVβ integrins oedema, and angiogenesis [13,23], and it is expressed and 5 1 3 The interactions between cells and extracellular matrix upregulated by several HHV-8 proteins including vIL-6 molecules (ECM) are mediated by cell membrane recep- and vGPCR and plays a significant part in the develop- tors belonging to the integrin family, that mediate cellular ment of KS [65]. migration and growth [72,73]. The increased levels of inflammatory cytokines and bFGF found in HIV-KS MMPs lesions upregulate the expression of α β and αVβ MMPs are a family of proteolytic enzymes involved in 5 1 3 integrins on HIV-KS cells [74]. degradation of extracellular matrix and basement mem- brane components. MMP gene expression is induced by a In HIV-seropositive subjects, extracellular HIV Tat protein variety of stimuli including inflammatory cytokines, binds to α β and αVβ integrin receptors on KS endothe- ECM-integrin interaction, growth factors, HIV Tat protein 5 1 3 lial and spindle cells, to provide them with the necessary and HHV-8 proteins [13,65,75]. MMP-2 is upregulated in signals for adhesion that is required for their subsequent HIV-KS lesions and it may play a rôle in inducing vascular proliferation in response to mitogenic stimuli by bFGF. permeability and oedema and in promoting endothelial HIV Tat protein also induces the synthesis of MMP-2 and cell growth, angiogenesis and tumour invasion MMP-9. The increased expression of MMPs in HIV-KS [74,84,85]. cells may lead to degradation of extracellular matrix com- ponents, facilitating the locomotion of endothelial cells Oxidative and nitrative metabolites in the and invasion of spindle cells [61,74,75]. pathogenesis of HIV-KS Persistent inflammatory state is conducive to the produc- In HIV-seronegative subjects with KS, cellular growth and tion of ongoing reactive oxidative and nitrative metabo- migration, and the expression of MMPs are induced by lites which are associated with tumourgenesis. They (α β )-fibronectin and (αVβ )-vitronectin interactions in promote cell proliferation, initiate nuclear and mitochon- 5 1 3 the presence of bFGF. The presence of HIV Tat protein in drial DNA mutations, induce a proangiogenic environ- HIV-KS fortifies the α β and αVβ stimulation [76,77]. ment, and inactivate DNA repair enzymes [71,86]. 5 1 3 This might explain the increased frequency of KS and the Page 3 of 9 (page number not for citation purposes) Infectious Agents and Cancer 2008, 3:1 http://www.infectagentscancer.com/content/3/1/1 HIV-seropositive subjects have high tissue levels of reac- secondly, HHV-8 specific – CD8 + cytotoxic T lymphocyte tive oxidative and nitrative metabolites owing to response is improved following HAART [13,88,89] and increased levels of proinflammatory cytokines, more fre- therefore there is a reduction in HHV-8 load. Thirdly, quent opportunistic infections and a reduction in the some protease inhibitors that are administered as a com- activity of antioxidant enzymes [87]. HIV-KS lesional cells ponent of HAART have anti-inflammatory and anti-ang- express endogenous oxidative and nitrative metabolites iogenic activity, thus directly inhibiting HIV-KS [10]. which together with increased exogenous oxidative and nitrative metabolite levels, associated with HIV infection, However, despite otherwise effective HAART, established may promote the particular aggressiveness of KS in HIV- HIV-KS may not always regress, and new KS lesions may seropositive subjects [71]. appear [13,54], perhaps as a manifestation of immune reconstitution inflammatory syndrome (IRIS) [30,33,55,56,59]. HIV infection, HAART and KS HIV infection may directly and indirectly promote the ini- tiation and progression of KS. HIV Tat protein, a transcrip- HIV associated IRIS IRIS can be defined as an exuberant immune-mediated tional activator of HIV gene expression, is a major factor implicated in the pathogenesis of HIV-KS [82]. Tat protein inflammatory response to a pre-existing subclinical path- is released by HIV-infected T cells. In this extracellular ogen or tumour antigen after treatment has brought about form, Tat synergises with inflammatory cytokines, which an improvement in a host previously profoundly are upregulated in HIV-KS lesions, to promote angiogen- depressed immunity [55,59,90]. In the context of HIV esis, and progression of HIV-KS. It does this by the induc- infection, HAART-induced IRIS has been described in rela- tion and mobilization of bFGF, and by interacting with tion to opportunistic infections including herpes simplex α β and αVβ integrins on both endothelial and spindle (HS), herpes zoster (HZ), mycobacterium tuberculosis, in 5 1 3 cells [75,80]. The coordinated signalling to endothelial relation to autoimmune thyroid disease, and in relation cells integrins α β and αVβ and growth factor receptors to KS. HIV-IRIS occurs paradoxically despite a reduction 5 1 3 by Tat protein and bFGF respectively, are important events in HIV load and improvement in all HIV related immuno- in the pathogenesis of HIV-KS [12,76]. logic parameters early after the introduction of HAART, and is probably the result of reconstituted pathogen-spe- By binding to α β and αVβ integrins on inflammatory cific immune responses [33,89,91-96]. However, the 5 1 3 cytokine-activated endothelial cells, Tat protein activates details regarding the immunopathogenic mechanisms the cascade of events in the FAS-ERK-MAPK intracellular that bring about IRIS are speculative [96]. signal transduction pathway. This promotes the progres- sion of KS endothelial cells through the G1 cell cycle In HIV-seropositive subjects who start HAART at an early phase in response to bFGF stimulation, and results in stage of HIV infection, the number and function of CD4+ increased cell proliferation [76]. In addition, Tat protein T cells tend to return to normal. On the other hand, sub- may act as an antiapoptotic agent causing prolonged sur- jects who start HAART, when the HIV infection is moder- vival of endothelial cells [67]. It also has the capacity to ately advanced (CD4+ T cell counts are between 100 × 6 6 regulate the cycle of HHV-8 growth and to reactivate latent 10 /L and 300 × 10 /L), will not show a similar recovery. HHV-8 infection [9,13]. A further outcome of the activity However, even such a partial immune reconstitution of Tat protein can be an increase in the synthesis of MMP- results in a profound decline in HIV-associated morbidity 2 by monocytes and by endothelial cells leading to and mortality [97]. increased vascular permeability and oedema [74]. CD4+ T cell restoration in peripheral blood after HAART HIV infection may indirectly affect the course of HIV-KS is biphasic. An initial rapid increase during the first 12 by perpetuating immunosuppression and immunodys- weeks of treatment is followed by a more gradual increase regulation, characterized by increased production of over the remainder of the first year, and after that there is proinflammatory cytokines that sustain the KS [13]. usually no further significant improvement. The initial- Moreover, Tat protein induces in monocyte-derived den- phase increase in the CD4+ T cells is due to proliferation dritic cells an increase in production of Th1 type cytokines and reduced apoptosis of existing memory cells in the cir- and β chemokines [77]. culation and to redistribution of CD4+ T cells from the lymph nodes into the circulation. Only after several Following the introduction of HAART sometimes estab- months of HAART, will T lymphoiesis associated with lished HIV-KS may regress and the likelihood of develop- improvement of thymic function become evident, giving ing new lesions of KS is diminished [5,9,13,38,40]. This rise to increased numbers of naïve T lymphocytes [89,97- can be attributed to three factors. Firstly, the reduction in 105]. With continued HAART there will also be an HIV load, Tat protein and inflammatory cytokines [13], increase in CD8+ T cells in the circulation lagging behind Page 4 of 9 (page number not for citation purposes) Infectious Agents and Cancer 2008, 3:1 http://www.infectagentscancer.com/content/3/1/1 the peak increase in CD4+ T cells by a period of about 5 opment of HIV-KS. The decline in the incidence of HIV- weeks. During the initial immune reconstitution phase KS, and the regression of KS in some HIV-seropositive the ability of the host to mount immuno-inflammatory subjects after the introduction of HAART, suggests that responses is restored [33,106], owing to the partial recov- some general improvement in immunity and in the recov- ery of CD4+ T cells and CD8+ cytotoxic T cell responses, ery of HHV-8-specific, MHC class I-restricted cytotoxic and the shift from a Th-2- to a Th-1-dominant cytokine CD8+ T cell response could be important in the control of profile. HHV-8 replication [114,115]. The CD4+ and CD8+ T cells that increase shortly after the introduction of HAART are All HIV-IRIS events occur in subjects who display as indi- memory cells. It is probable that in HIV-seropositive sub- cators of immune reconstitution, a decrease in HIV viral jects who are commonly latently or subclinically coin- load and an increase in CD4+ T cell count. HIV-seroposi- fected with HHV-8, the HHV-8-specific cytotoxic T cells tive subjects with IRIS episodes tend to be younger at the lodge in sites of HHV-8 subclinical infection, or in sites of time of introduction of HAART and tend to have a lower established KS lesions. In most of HIV-seropositive sub- median baseline CD4+ T cell percentage than HIV-serop- jects, these CD8+ T cells will be protective and will control ositive subjects who do not experience IRIS. Overall, the HHV-8 replication and spread, thus reducing the inci- median time to onset of IRIS in those subjects who display dence of new KS lesions, and at times bringing about this response is 12 weeks [92-96]. regression in established KS lesions. However in a minor- ity of HIV-seropositive subjects with subclinical HHV-8 HIV-seropositive subjects who are at greater risk for devel- infection, or with established KS, such an immune oping IRIS are those with low CD4+ T cell counts of < 100 response may be dysregulated and accompanied by an cells/ul [95,107], those with CD4+ T cell percentage of intensified HHV-8-specific inflammatory response para- <10%, and those of a younger age at the time of introduc- doxically causing a worsening of KS and as a consequence, tion of HAART [96]. There is no association between the the development of IRIS-KS [112]. risk for developing IRIS and the magnitude of the increase in CD4+ T cell count or the percentage of CD4+ T cell There could be other mechanisms that may be involved in increase, and the plasma load decrease following HAART the pathogenesis of IRIS-KS. As part of the immune resto- [95,96,108] In contrast, Shelburne et al.[94] and Breton et ration after HAART, there is a shift in the cytokine profile al.[109] found that HIV-IRIS is associated with a greater from the Th-2 to the Th-1 type. Th-1 cytokines have the increase in the percentage of CD4+ T cell one month after capacity to reactivate latent HHV-8 in blood and tissue the introduction of HAART and with a more pronounced cells, and as a consequence, HHV-8 can spread to unin- and persistent reduction in HIV load. Thus, there is some fected endothelial cells. Perhaps in a subset of HIV-serop- conflict in the immunological parameters associated with ositive subjects, the restored HHV-8-specific immune the development of HIV-IRIS. response following HAART is ineffective in controlling the increased HHV-8 antigens in blood and tissue cells, and as The definite association of the events of HIV-IRIS with a a result, paradoxically promotes the development of IRIS- low baseline CD4+ T cell percentage probably reflects a KS. higher burden of opportunistic subclinical pathogens at the time of HAART introduction. Such a high burden of Because of the inability of the immune response to con- antigenic stimulation together with a dysregulated trol the HHV-8 infection, two processes may occur in par- increased immune response during immunoreconstitu- allel; the development of an exaggerated tion after HAART, may be responsible for the develop- immunoinflammatory reaction characterized by the ment of HIV-IRIS [90]. increased production of inflammatory cytokines in order to combat HHV-8; and secondly, the increase in the HHV- The immunopathogenic mechanisms associated with IRIS 8 load in the tissues through autocrine and paracrine differ according to the type of pathogen involved [90]. mechanisms increase the production of inflammatory CD8+ cytotoxic T cell response is associated with IRIS cytokines, chemokines and growth factors. Together these induced by viral infections [110,111] and a delayed type- processes upregulate the expression of αvβ and α β , and 3 5 1 hypersensitivity or a lymphoproliferative reaction with MMPs that induce the IRIS-KS angioproliferation and IRIS induced by mycobacterial infections [90,112,113]. tumourigenesis [55]. In this context, HIV Tat protein and a profound state of immunosuppression do not signifi- IRIS associated HIV-KS cantly affect the development of IRIS-KS. Most HIV-seropositive subjects with KS do not demon- strate HHV-8-specific cytotoxic T lymphocyte response. Bower et al. [33], reported that 10 of 150 (6.6%) HAART- This lack of HHV-8-specific cellural immune response naïve HIV-seropositive subjects with KS either developed during HIV infection is a contributory factor in the devel- new KS lesions or exhibited rapid progression of existing Page 5 of 9 (page number not for citation purposes) Infectious Agents and Cancer 2008, 3:1 http://www.infectagentscancer.com/content/3/1/1 clinicopathologic study. Oral Surg Oral Med Oral Pathol Oral Radiol KS lesions within 2 months of starting HAART. These sub- and Endod 1997, 83:259-264. jects had a significantly higher CD4+ T cell count at the 9. Von Roenn JH: Clinical presentations and standard therapy of time of IRIS-KS diagnosis and a higher frequency of KS- AIDS-associated Kaposi's sarcoma. Hematol Oncol Clin North Am 2003, 17:747-762. associated oedema than HIV-seropositive subjects with KS 10. Monini P, Sgadari C, Barillari G, Ensoli B: HIV protease inhibitors: who did not develop IRIS. antiretroviral agents with anti-inflammatory, anti-ang- iogenic and anti-tumour activity. J Antimicrob Chemother 2003, 51:207-211. Summary 11. Hengge UR, Ruzicka T, Tyring SK, Stuschke M, Roggendorf M, The clinical course of HIV-KS is unpredictable. For some Schwartz RA, et al.: Update on Kaposi's sarcoma and other HHV8 associated diseases. Part 2: Pathogenesis, Castle- HIV-seropositive subjects, KS is a mild disease, while for man's disease and pleural effusion lymphoma. Lancet Infect Dis others it may be rapidly progressive and aggressive. 2002, 2:344-352. Regression of HIV-KS lesions and a substantial decrease in 12. Ensoli B, Sgadari C, Barillari G, Sirianni MC, Sturzl M, Monini P: Biol- ogy of Kaposi's sarcoma. Eur J Cancer 2001, 37:1251-69. the incidence of HIV-KS occur after the introduction of 13. Krown SE: Therapy of AIDS-associated Kaposi's sarcoma: tar- HAART. However, a small subset of HIV-seropositive sub- geting pathogenetic mechanisms. Hematol Oncol Clin North Am 2003, 17:763-783. jects with a low CD4 + T cell count at the time of HAART 14. Schwartz RA: Kaposi's sarcoma: An update. J Surg Oncol 2004, initiation, may develop IRIS associated HIV-KS shortly 87:146-151. thereafter. 15. Foreman KE, Friborg J, Chandran B, Katano H, Sata T, Mercader M, Nabel GJ, Nickoloff BJ: Injection of human herpesvirus-8 in human skin engrafted on SCID induces Kaposi's sarcoma- IRIS-KS is not a specific entity but it is a phenomenon like lesions. J Dermatol Sci 2001, 26:182-193. 16. Feller L, Lemmer J, Wood NH, Raubenheimer EJ: Necrotizing gin- which can be recognized by certain well defined circum- givitis of Kaposi sarcoma affected gingivae. SADJ 2006, stances: the presence of low CD4+ T cell counts at the time 61:314-317. of introduction of HAART; a temporal relationship 17. Moore PS, Chang Y: Detection of herpesvirus-like DNA sequences in Kaposi's sarcoma in patients with and without between rapid clinical progression of KS and the develop- HIV infection. N Eng J Med 1995, 332:1182-1185. ment of new KS lesions usually of about 8 weeks (though 18. Huang YQ, Li JJ, Kaplan MH, Poiesz B, Katabira E, Zhang WC, et al.: this period may range from 3 weeks to 22 weeks) after the Human herpesvirus-like nucleic acid in various forms of Kaposi's sarcoma. Lancet 1995, 345:759-761. initiation of HAART; and the suppression of HIV load and 19. Forman KE, Bacon PE, Hsi ED, Nickoloff BJ: In situ polymerase restoration of CD4+ T cell count. chain reaction-based localization studies support role of human herpes virus-8 as the cause of two AIDS-related neo- plasms: Kaposi's sarcoma and body cavity lymphoma. J Clin Competing interests Invest 1997, 99:2971-2978. The author(s) declare that they have no competing inter- 20. Whitby D, Howard MR, Tenant-Flowers M, Brink NS, Copas A, Boshoff C, et al.: Detection of Kaposi sarcoma associated her- ests. pesvirus in peripheral blood of HIV-infected individuals and progression of Kaposi sarcoma. Lancet 1995, 346:799-802. 21. Moore PS, Kingsley LA, Holmberg SD, Spira T, Gupta P, Hoover DR, References et al.: Kaposi's sarcoma-associated herpesvirus infection prior 1. Leao JC, Caterino-de-Araujo A, Porter SR, Scully C: Human her- to onset of Kaposi's sarcoma. AIDS 1996, 10:175-180. pesvirus 8 (HHV-8) and the etiopathogenesis of Kaposi's sar- 22. Cattelan A, Calabro ML, Gasperini P, Aversa SM, Zanchetta M, coma. Rev Hosp Clin Fac Med Sao Paulo 2002, 57:175-186. Meneghetti F, et al.: Acquired immunodeficiency syndrome- 2. Tappero JW, Conant MA, Wolfe SF, Berger TG: Kaposi's sarcoma. related Kaposi's sarcoma regression after highly active Epidemiology, pathogenesis, histology, clinical spectrum, antiretroviral therapy: biologic correlates of clinical out- staging criteria and therapy. J Am Acad Dermatol 1993, come. J Natl Cancer Inst Monogr 2001, 27:44-49. 28:371-395. 23. Bubman D, Cesarman E: Pathogenesis of Kaposi's sarcoma. 3. Jensen KK, Manfra DJ, Grisotto MG, Martin AP, Vassileva G, Kelly K, Hematol Oncol Clin North Am 2003, 17:717-745. et al.: The human herpes virus 8-encoded chemokine recep- 24. Engels EA, Biggar RJ, Marshall VA, Walters MA, Gamade CJ, Whitby tor is required for angioproliferation in a murine model of D, et al.: Detection and quantification of Kaposi's sarcoma Kaposi's sarcoma. J Immunol 2005, 174:3686-3694. associated herpes virus to predict AIDS-associated Kaposi's 4. Feller L, Jadwat Y, Raubenheimer EJ: Kaposi sarcoma and calcium sarcoma. AIDS 2003, 17:1847-1851. channel blocker-induced gingival enlargement occurring 25. Simpson GR, Schultz TF, Whitby D, Cook PM, Boshoff C, Rainbow L, simultaneously: Review of the literature and report of a case. et al.: Prevalence of Kaposi's sarcoma associated herpesvirus Oral Biosci Med 2004, 4:291-297. infection measured by antibodies to recombinant caspid 5. Gallafent JH, Buskin SE, De Turk PB, Aboulafia DM: Profile of protein and latent immunofluorescence antigen. Lancet 1996, patients with Kaposi's Sarcoma in the era of highly active 348:1133-1138. antiretroviral therapy. J Clin Oncol 2005, 23:1253-1260. 26. Gao SJ, Kingsley L, Hoover DR, Spiro TJ, Rinaldo CR, Saah A, et al.: 6. Fauci AS, Lane HC: Human immunodeficiency virus disease: Seroconversion to antibodies against Kaposi's sarcoma-asso- Aids and related disorders. In Harrison's Principles of Internal Med- ciated herpesvirus-related latent nuclear antigens before the icine 16th edition. Edited by: Kasper DL, Braunwald E, Fauci AS, development of Kaposi's sarcoma. N Engl J Med 1996, Hauser SL, Longo DL, Jameson JL. New York: McGraw-Hill; 335:233-241. 2005:1076-1139. 27. Verbeek W, Frankel M, Miles S, et al.: Seroprevalence of HHV-8 7. Hengge UR, Ruzicka T, Tyring SK, Stuschke M, Roggendorf M, antibodies in HIV-positive homosexual men without Schwartz RA, et al.: Update on Kaposi's sarcoma and other Kaposi's sarcoma and their clinical follow-up. Am J Clin Pathol HHV8 associated diseases. Part 1: Epidemiology, environ- 1998, 109:778-783. mental predispositions, clinical manifestations and therapy. 28. Mendez JC, Procop GW, Espy MJ, Paya CV, Smith TF: Detection Lancet Infect Dis 2002, 2:281-292. and semiquantitative analysis of human herpesvirus 8 DNA 8. Flaitz CM, Jin YT, Hicks MJ, Nichols CM, Wang YW, Su IJ: Kaposi's in specimens from patients with Kaposi's sarcoma. J Clin sarcoma associated herpesvirus-like DNA sequences Microbiol 1998, 36:2220-2222. (KSHV/HHV-8) in oral AIDS-Kaposi's sarcoma: a PCR and Page 6 of 9 (page number not for citation purposes) Infectious Agents and Cancer 2008, 3:1 http://www.infectagentscancer.com/content/3/1/1 29. Iscovich J, Boffetta P, Franceschi S, Azizi E, Sarid R: Classic Kaposi active antiretroviral therapy. J Invest Dermatol 2001, sarcoma: Epidemiology and risk factors. Cancer 2000, 117:858-863. 88:500-517. 48. Leitch H, Trudeau M, Routy JP: Effect of protease inhibitor-based 30. Connick E, Kane MA, White IE, Ryder J, Campbell TB: Immune highly active antiretroviral therapy on survival in HIV-associ- reconstitution inflammatory syndrome associated with ated advanced Kaposi's sarcoma patients treated with Kaposi sarcoma during potent antiretroviral therapy. Clin chemotherapy. HIV Clin Trials 2003, 4:107-114. Infect Dis 2004, 39:1852-1855. 49. Bower M, Fox P, Fife K, Gill J, Nelson M, Gazzard B, et al.: Highly 31. Ensoli B, Barillari G, Salahuddin SZ, Gallo RC, Wong-Staal F: Tat pro- active anti-retroviral therapy (HAART) prolongs time to tein of HIV-1 stimulates growth of cells derived from treatment failure in Kaposi's sarcoma. AIDS 1999, Kaposi's sarcoma lesions of AIDS patients. Nature 1990, 13:2105-2111. 345:84-86. 50. Martinelli C, Zazzi M, Ambu S, Bartolozzi D, Corsi P, Leoncini F: 32. Ensoli B, Gendelman R, Markham P, Fiorelli V, Columbini S, Raffeld M, Complete regression of AIDS-related Kaposi's sarcoma- et al.: Synergy between basic fibroblast growth factor and the associated human herpesvirus-8 during therapy with indina- HIV-1 Tat protein in induction of Kaposi's sarcoma. Nature vir. AIDS 1998, 12:1717-1719. 1994, 371:674-680. 51. Paparizos VA, Kyriakis KP, Papastamopoulos V, Hadjivassiliou M, Sta- 33. Bower M, Nelson M, Young AM, Thirlwell C, Newsom-Davis T, Man- vrinaes NG: Response of AIDS-associated Kaposi sarcoma to dalia S, et al.: Immune reconstitution inflammatory syndrome highly active antiretroviral therapy alone. J Acquir Immune Defic associated with Kaposi's sarcoma. J Clin Oncol 2005, Syndr 2002, 30:257-258. 23:5224-5228. 52. Winceslaus J: Regression of AIDS-related pleural effusion with 34. Palellla FJ Jr, Delaney KM, Marman AC, Loveless MO, Fuhreh J, Salten HAART: highly active antiretroviral therapy. Int J STD AIDS GA, et al.: Declining morbidity and mortality among patients 1998, 9:368-370. with advanced human immunodeficiency virus infection. 53. Boshoff C, Weiss R: AIDS-related malignancies. Nat Rev Cancer HIV Outpatient Study Investigators. N Engl J Med 2003, 2002, 2:373-382. 338:853-860. 54. Nasti G, Martellotta F, Beretta M, Menna M, Fasan M, Di Perri G, et 35. Portsmouth S, Stebbing J, Gazzard B: Current treatment of HIV al.: Impact of highly active antiretroviral therapy on the pre- infection. Curr Top Med Chem 2003, 3:1458-1466. senting features and outcome of patients with acquired 36. Autran B, Carcelain G, Li TS, Blanc C, Mathez D, Tubiana R, et al.: immunodeficiency syndrome-related Kaposi's sarcoma. Can- Positive effects of combined antiretroviral therapy on CD4+ cer 2003, 98:2440-2446. T cell homeostasis and function in advanced HIV disease. Sci- 55. Leidner RS, Aboulafia DM: Recrudescent Kaposi's sarcoma after ence 1997, 277:112-116. initiation of HAART: A manifestation of immune reconstitu- 37. Quinlivan EB, Zhang C, Stewart PW, Komoltri C, Davis MG, Wehbie tion syndrome. Aids patient care STD 2005, 19:635-644. RS: Elevated virus loads of Kaposi's sarcoma-associated 56. Shelburne SA 3rd, Hamill RJ, Rodriguez-Barradas MC, Greenberg SB, human herpesvirus 8 predict Kaposi's sarcoma disease pro- Atmor RL, Musher DW, et al.: Immune reconstitution inflamma- gression, but elevated levels of human immunodeficiency tory syndrome: emergence of a unique syndrome during virus type 1 do not. J Infect Dis 2002, 185:1736-1744. highly active antiretroviral therapy. Medicine 2002, 81:213-227. 38. Jones JL, Hanson DL, Dworkin MS, Jaffe HW, et al.: Incidence and 57. Weir A, Wansbrough-Jones M: Mucosal Kaposi's sarcoma fol- trends in Kaposi's sarcoma in the era of effective antiretrovi- lowing protease inhibitor therapy in an HIV-infected patient. ral therapy. J Acquir Immune Defic Syndr 2000, 24:270-274. AIDS 1997, 11:1895-1896. 39. Hermans P, Lundgren J, Sommereijns B, Katlama C, Chiesi A, Goebel 58. Rizos E, Drosos AA, Ioannidis JP: Isolated intraparotid Kaposi FD, et al.: Survival of European patients with Kaposi's sarcoma sarcoma in human immunodeficiency virus type 1 infection. as AIDS-defining condition during the first decade of AIDS. Mayo Clin Proc 2003, 78:1561-1563. AIDS in Europe study group. AIDS 1997, 11:525-531. 59. Crane HM, Deubner H, Huang JC, Swanson PE, Harrington RD: Fatal 40. Portsmouth S, Stebbing J, Gill J, Mandalia S, Bower M, Nelson M, et al.: Kaposi's sarcoma-associated immune reconstitution follow- A comparison of regimens based on non-nucleoside reverse ing HAART initiation. Int J STD AIDS 2005, 16:80-83. transcriptase inhibitors or protease inhibitors in preventing 60. Mallery SR, Pei P, Kang J, Zhu G, Ness GM, Schwendeman SP: Sus- Kaposi's sarcoma. AIDS 2003, 17:F17-22. tained antiogenesis enable in vivo transplantation of muco- 41. Jacobson LP, Yamashita TE, Detels R, Margolick JB, Chmiel JS, Kings- cutaneous derived AIDS-related Kaposi's sarcoma cells in ley LA, et al.: Impact of potent antiretroviral therapy on the murine hosts. Carcinogenesis 2000, 21:1647-1653. incidence of Kaposi's sarcoma and non-Hodgkin's lympho- 61. Barillari G, Ensoli B: Angiogenic effects of extracellular human mas among HIV-1-infected individuals. J Acquir Immun Defic immunodeficiency virus type 1 Tat protein and its role in the Syndr 1999, 21:S34-41. pathogenesis of AIDS-associated Kaposi's sarcoma. Clin 42. International Collaboration on HIV and Cancer: Highly active Microbiol Rev 2002, 15:310-326. antiretroviral therapy and incidence of cancer in human 62. Sodhi A, Montaner S, Gutkind JS: Does dysregulated expression immunodeficiency virus-infected adults. J Natl Cancer Institute of a deregulated viral GPCR trigger Kaposi's sarcomagene- 2000, 92:1823-1830. sis? FASEB J 2004, 18:422-427. 43. Lebbe C, Blum L, Pellet C, Blanchard G, Verola O, Morel P, et al.: 63. Sodhi A, Montaner S, Patel V, Gomez-Roman JJ, Li Y, Sausville EA, et Clinical and biological impact of antiretroviral therapy with al.: Akt plays a central role in sarcomagenesis induced by protease inhibitors on HIV-related Kaposi's sarcoma. AIDS Kaposi's sarcoma herpesvirus-encoded G protein-coupled 1998, 12:F45-49. receptor. Proc Natl Acad Sci USA 2004, 101:4821-4826. 44. Cattelan AM, Calabro ML, Aversa SM, Zanchetta M, Meneghetti F, De 64. Sodhi A, Montaner S, Patel V, Zohar M, Bais C, Mesri EA, et al.: The Rossi A, et al.: Regression of AIDS-related Kaposi's sarcoma Kaposi's sarcoma-associated herpes virus G protein-coupled following antiretroviral therapy with protease inhibitors: receptor up-regulates vascular endothelial growth factor biological correlates of clinical outcome. Eur J Cancer 1999, expression and secretion through mitogen-activated protein 35:1809-1815. kinase and p38 pathways acting on hypoxia-inducible factor 45. Aboulafia DM: The epidemiologic, pathologic, and clinical fea- 1 alpha. Cancer Res 2000, 60:4873-4880. tures of AIDS-associated pulmonary Kaposi's sarcoma. Chest 65. Naranatt PP, Krishnan HH, Svojanovsky SR, Bloomer C, Mathur S, 2000, 117:1128-1145. Chandran B: Host gene induction and transcriptional repro- 46. Holkova B, Takeshita K, Cheng DM, Volm M, Wasserheit C, Demo- gramming in Kaposi's sarcoma-associated herpesvirus poulos R, et al.: Effect of highly active antiretroviral therapy on (KSHV/HHV-8)-infected endothelial, fibroblast, and B cells: survival in patients with AIDS-associated pulmonary insights into modulation events early during infection. Cancer Kaposi's sarcoma treated with chemotherapy. J Clin Oncol Res 2004, 64:72-84. 2001, 19:3848-3851. 66. Ensoli B, Sturzl M, Monini P: Reactivation and role of HHV-8 in 47. Pellet C, Chevret S, Blum L, Gauville C, Hurault M, Blanchard G, et al.: Kaposi's sarcoma initiation. Adv Cancer Res 2001, 81:161-200. Virologic and immunologic parameters that predict clinical 67. Buttiglieri S, Deregibus MC, Bravo S, Cassoni P, Chiarle R, Bussolati response of AIDS-associated Kaposi's sarcoma to highly B, et al.: Role of Pax 2 in apoptosis resistance and proinvasive Page 7 of 9 (page number not for citation purposes) Infectious Agents and Cancer 2008, 3:1 http://www.infectagentscancer.com/content/3/1/1 phenotype of Kaposi's sarcoma cells. J Biol Chem 2004, expression of αvβ3 and α5β1 integrins during human 279:4136-4143. melanoma cell invasion. Cancer Res 1993, 53:3411-3415. 68. Schwartz M, Murphy PM: Kaposi's sarcoma-associated herpesvi- 86. Wink DA, Vodovotz Y, Laval J, Laval F, Dewhirst MW, Mitchell JB: rus G protein-coupled receptor constitutively activates NF- The multifaceted roles of nitric oxide in cancer. Carcinogenesis B and induces proinflammatory cytokine and chemokine 1998, 19:711-721. production via a c-terminal signaling determinant. J Immunol 87. Lucey DR, Clerici M, Shearer GM: Type 1 and Type 2 cytokine 2001, 167:505-513. dysregulation in human infectious, neoplastic and inflamma- 69. Rabkin CS, Janz S, Lash A, Coleman AE, Musaba E, Liotta L, et al.: tory diseases. Clin Microbiol Rev 1996, 9:532-562. Monoclonal origin of muilticentric Kaposi's sarcoma lesions. 88. Wilkinson J, Cope A, Gill J, Bourboulia D, Hayes P, Imami N, et al.: N Engl J Med 1997, 336:988-993. Identification of Kaposi's sarcoma-associated herpesvirus 70. Gill PS, Tsai YC, Rao AP, Spruck CH 3rd, Zheng T, Harrington WA (KSHV)-specific responses in human immunodeficiency Jr, et al.: Evidence for multiclonality in multicentric Kaposi's virus type 1-Infected patients receiving highly active antiret- sarcoma. Proc Natl Acad Sci USA 1998, 95:8257-8261. roviral therapy. J Virol 2002, 76:2634-2640. 71. Mallery SR, Pei P, Landwehr DJ, Clark CM, Bradburn JE, Ness GM, et 89. Robertson P, Scadden DT: Immune reconstitution in HIV infec- al.: Implications for oxidative and nitrative stress in the tion and its relationship to cancer. Hematol Oncol Clin North Am pathogenesis of AIDS-related Kaposi's sarcoma. Carcinogene- 2003, 17:703-716. sis 2004, 25:597-603. 90. Cheng VCC, Yuen KY, Chan WM, Wong SSY, Ma ESK, Chan RMT: 72. Hynes RO: Integrins: versatility, modulation and signaling in Immunorestitution disease involving the innate and adaptive cell adhesion. Cell 1992, 69:11-25. response. Clin Infec Dis 2000, 30:882-892. 73. Barillari G, Albonici L, Incerpi S, Bogetto L, Pistritto G, Volpi A, et al.: 91. Jubault V, Penfornis A, Schillo F, Hoen B, Izembart M, Timsit J, et al.: Inflammatory cytokines stimulate vascular smooth muscle Sequential occurrence of thyroid autoantibodies and Grave's cells locomotion and growth by enhancing α5β1 integrin disease after immune restoration in severely immunocom- expression and function. Atherosclerosis 2001, 154:377-385. promised human immunodeficiency virus-1 infected 74. Toschi E, Barillari G, Sgadari C, Bacigalupo I, Ceresto A, Carlei D, et patients. J Clin Endocrinal Metab 2000, 85:4254-4257. al.: Activation of matrix-metalloproteinase-2 and mem- 92. Lawn SD, Bekker LG, Miller RF: Immune reconstitution disease brane-type-1-matrix-metalloproteinase in endothelial cells associated with mycobacterial infections in HIV-infected and induction of vascular permeability in vivo by human individuals receiving antiretrovirals. Lancet Infect Dis 2005, immunodeficiency virus-1 Tat protein and basic fibroblast 5:361-373. growth factor. Mol Biol Cell 2001, 12:2934-2946. 93. Shelburne SA 3rd, Hamill RJ: The immune reconstitution inflam- 75. Barillari G, Sgadari C, Fiorelli V, Samaniego F, Colombini S, Manzari V, matory syndrome. AIDS Rev 2003, 5:67-79. et al.: The Tat protein of human immunodeficiency virus 94. Shelburne SA, Visnegarwala F, Darcourt J, Gravis EA, Giordano TP, type-1 promotes vascular cell growth and locomotion by White AC: Incidence and risk factors for immune reconstitu- engaging the α5β1 and αvβ3 integrins and by mobilizing tion inflammatory syndrome during highly active antiretro- sequestered basic fibroblast growth factor. Blood 1999, viral therapy. AIDS 2005, 19:399-406. 94:663-672. 95. French MA, Lenzo N, John M, Mallai SA, McKinnin EJ, James IR, et al.: 76. Toschi E, Bacigalupo I, Strippoli R, Chiozzini C, Cereseto A, Falchi M, Immune restoration disease after the treatment of immun- et al.: HIV-1 Tat regulates endothelial cell cycle progression odeficient HIV-infected patients with highly active antiretro- via activation of the Ras/ERK MAPK signaling pathways. Mol viral therapy. HIV Med 2000, 1:107-115. Biol Cell 2006, 17:1985-1994. 96. Ratnam I, Chiu C, Kandala NB, Easterbrook PJ: Incidence and risk 77. Fanales Belasio E, Moretti S, Nappi F, Barillari G, Micheletti F, Cafaro factors for immune reconstitution inflammatory syndrome A, et al.: Native HIV-Tat protein targerts monocyte-derived in an ethnically diverse HIV type-1-infected cohorot. Clin dendritic cells and enhances their maturation, function, and Infect Dis 2006, 42:418-427. antigen-specific T cell responses. J Immunol 2002, 168:197-206. 97. Valdez H, Connick E, Smith KY, Leerman MM, Bosch RJ, Kim RS, et 78. Lamoreaux WJ, Fitzgerald ME, Reiner A, Hasty KA, Charles ST: Vas- al.: Limited immune restoration after 3 years' suppression of cular endothelial growth factor increases release of gelati- HIV-1 replication in patients with moderately advanced dis- nase A and decrease release of tissue inhibitor of ease. AIDS 2002, 16:1859-1866. metalloproteinases by microvascular endothelial cells in 98. Douek DC, McFarland RD, Keiser PH, Cage FA, Massey JM, Haynes vitro. Microvasc Res 1998, 55:29-42. BF, et al.: Changes in thymic function with age and during 79. Blotnick S, Peoples GE, Freeman MR, Eberlein TJ, Klagsbrun M: T- treatment of HIV infection. Nature 1998, 396:690-695. lymphocytes synthesize and export heparin-binding epider- 99. Zhang I, Lewin SR, Markowitz M, Linn HH, Skulski E, Karanicolas R, et mal growth factor-like growth factor, and basic fibroblast al.: Measuring recent thymic emigrants in blood of normal growth factor, mitogens for vascular cells and fibroblasts: dif- and HIV-1-infected individuals before and after effective ferential production and release by CD4+ and CD8+ T cells. therapy. J Exp Med 1999, 190:725-732. Proc Natl Acad Saci USA 1994, 91:2890-2894. 100. Carcelain G, Debre P, Autran B: Reconstitution of CD4+ T lym- 80. Barillari G, Sgadari C, Palladino C, Gendelman R, Caputo A, Morris phocytes in HIV-infected individuals following antiretroviral CB, et al.: Inflammatory cytokines synergize with HIV-1 Tat therapy. Curr Opin Immunol 2001, 13:483-488. protein to promote angiogenesis and Kaposi's sarcoma via 101. Carcelain G, Tubiana R, Samri A, Calvez V, Delaugerre C, Augut H, et induction of basic fibroblast growth factor and αvβ3 integrin. al.: Transient mobilization of human immunodeficiency virus J Immunol 1999, 15:1929-1935. (HIV) – specific CD4 T-helper cells fails to control virus 81. Samaniego F, Markham PD, Gallo RC, Ensoli B: Inflammatory rebounds during intermittent antiretroviral therapy in cytokines induce AIDS-Kaposi's sarcoma-derived spindle chronic HIV type 1 infection. J Virol 2001, 75:234-241. cells to produce and release basic fibroblast growth factor 102. Pakker NG, Notermans DW, be Boer RJ, Roos MT, de Wolf F, Hill and enhance Kaposi's sarcoma-like lesion formation in nude A, et al.: Biphasic kinetics of peripheral blood T cells after tri- mice. J Immunol 1995, 154:3582-3592. ple combination therapy in HIV-1 infection: a composite of 82. Bussolino F, Mitola S, Serini G, Barillari G, Ensoli B: Interactions redistribution and proliferation. Nat Med 1998, 4:208-214. between endothelial cells and HIV-1. Int J Biochem Cell Biol 2001, 103. Bucy RP, Hockett RD, Derdeyn CA, Saag MS, Squires K, Sillers M, et 33:371-390. al.: Initial increase in blood CD4(+) lymphocytes after HIV 83. Ferrari N, Morini M, Pfeffer U, Minghelli S, Noonan DM, Albini A: antiretroviral therapy reflects redistribution from lymphoid Inhibition of Kaposi's sarcoma in vivo by fenretinide. Clin Can- tissues. J Clin Invest 1999, 103:1391-1398. cer Res 2003, 9:6020-6029. 104. Connick E, Lederman MM, Kotzin BL, Spritzler J, Kuritzkes DR, St 84. Brooks PC, Stromblad S, Sanders LC, von Schalscha TL, Aimes RT, Clair M, et al.: Immune reconstitution in the first year of Stetler-Stevenson WG, et al.: Localization of matrix metallopro- potent antiretroviral therapy and its relationship to virologic teinase MMP-2 to the surface of invasive cells by interaction response. J Infec Dis 2000, 181:358-363. with integrin αvβ3. Cell 1996, 85:683-693. 105. Lederman MM, Connick E, Landay A, Kuritzkes DR, Spritzler J, St 85. Seftor RE, Seftor EA, Stetler-Stevenson WG, Welch DR, Hendrix MJ: Clair M, et al.: Immunologic responses associated with 12 The 72 kDa type IV collagenase is modulated via differential weeks combination antiretroviral therapy consisting of zido- Page 8 of 9 (page number not for citation purposes) Infectious Agents and Cancer 2008, 3:1 http://www.infectagentscancer.com/content/3/1/1 vudine, lamivudine and ritonavir: results of AIDS Clinical Trials Group Protocol 315. J Infect Dis 1998, 178:70-79. 106. Lederman MM: Immune restoration and CD4+ T-cell function with antiretroviral therapies. AIDS 2001, 15(Suppl 2):S11-15. 107. Jevtovic DJ, Salemovic D, Pesic I, Zerjav S, Djurkovic-Djakovic O: The prevalence and risk of immune restoration disease in HIV-infected patients treated with highly active antiretrovi- ral therapy. HIV Med 2005, 6:140-143. 108. Robertson J, Meier M, Wall J, Ying J, Fichtenbaum CJ: Immune reconstitution syndrome in HIV: Validating a case definition and identifying clinical predictors in persons initiating antiretroviral therapy. Clin Infect Dis 2006, 42:1639-1646. 109. Breton G, Duval X, Estellat C, Paoletti X, Bonnet D, Mvondo D, et al.: Determinants of immune reconstitution inflammatory syn- drome in HIV type-1-infected patients with tuberculosis after initiation of antiretroviral therapy. Clin Infect Dis 2004, 39:1709-1712. 110. Martinez E, Gatell J, Moran Y, Aznar E, Buira E, Guelar A, et al.: High incidence of herpes zoster in patients with AIDS soon after therapy with protease inhibitors. Clin Infect Dis 1998, 27:1510-1513. 111. Domingo P, Torres OH, Ris J, Vazquez G: Herpes zoster as an immune reconstitution disease after initiation of combina- tion antiretroviral therapy in patients with human immuno- deficiency virus type-1 infection. Am J Med 2001, 110:605-609. 112. Foudraine NA, Hovenkamp E, Natermans DW, Meenhorst PL, Klein MR, Lange JMA, et al.: Immunopathology as a result of highly active antiretroviral therapy in HIV-1-infeted patients. AIDS 1999, 13:177-184. 113. French MAH, Malal SA, Dawkins RL: Zidovudine-induced restora- tion of cell-mediated immunity to mycobacteria in immuno- deficient HIV-infected patients. AIDS 1992, 6:1293-1297. 114. Osman M, Kubo T, Gill J, Neipel F, Becker M, Smith G, et al.: Identi- fication of human herpesvirus 8-specific cytotoxic T-cell responses. J Virol 1999, 73:6136-6140. 115. Hirsh H, Kaufmann G, Sendi P, Battegay M: Immune reconstitu- tion in HIV-infected patients. Clin Infect Dis 2004, 38:1159-1166. Publish with Bio Med Central and every scientist can read your work free of charge "BioMed Central will be the most significant development for disseminating the results of biomedical researc h in our lifetime." 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