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REVIEW URRENT CD8 T-cell responses in HIV controllers: potential PINION implications for novel HIV remission strategies a,b c Rachel L. Rutishauser and Lydie Trautmann Purpose of review Immunological studies of spontaneous HIV and simian virus (SIV) controllers have identified virus-specific CD8 T cells as a key immune mechanism of viral control. The purpose of this review is to consider how knowledge about the mechanisms that are associated with CD8 T cell control of HIV/SIV in natural infection can be harnessed in HIV remission strategies. Recent findings We discuss characteristics of CD8 T-cell responses that may be critical for suppressing HIV replication in spontaneous controllers comprising HIV antigen recognition including specific human leukocyte antigen types, broadly cross-reactive T cell receptors and epitope targeting, enhanced expansion and antiviral functions, and localization of virus-specific T cells near sites of reservoir persistence. We also discuss the need to better understand the timing of CD8 T-cell responses associated with viral control of HIV/SIV during acute infection and after treatment interruption as well as the mechanisms by which HIV/SIV-specific CD8 T cells coordinate with other immune responses to achieve control. Summary We propose implications as to how this knowledge from natural infection can be applied in the design and evaluation of CD8 T-cell-based remission strategies and offer questions to consider as these strategies target distinct CD8 T-cell-dependent mechanisms of viral control. Keywords CD8 T cells, HIV controllers, HIV remission strategies INTRODUCTION: THE ROLE OF CD8 sizes [4,5]. Recently, a rare sub-group of elite con- T-CELL RESPONSES IN HIV CONTROLLERS trollers termed ‘exceptional’ elite controllers have been found to harbor an extremely small HIV res- In HIV infection as in any other viral infection, ervoir, thus achieving a state very close to a natural disease progression and outcome are highly variable HIV remission [5,6 ]. In addition to the individuals between individuals and a wide spectrum of viral who control HIV in the absence of ART, two small control exists that is dependent on virologic fea- tures, route of transmission, host genetics, immune responses and environment. While the vast majority Department of Medicine, University of California, San Francisco, San of people living with HIV are unable to suppress viral Francisco, California, Gladstone-UCSF Institute for Genomic Immu- replication without antiretroviral therapy (ART), a nology, San Francisco, CA, USA and Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, USA small group of people – less than 1% of people living Correspondence to Lydie Trautmann, EngD, PhD, 505 NW 185th Ave, with HIV-1 and 15% of people living with HIV-2, #1107D, Beaverton, OR 97006, USA. Tel: +1 503 418 2785; with an increased proportion of women – can nat- e-mail: firstname.lastname@example.org; Rachel L. Rutishauser, MD, PhD, 1001 urally keep the virus under control [1,2]. Over the Potrero Avenue, Building 3, Room 507, San Francisco, CA 94110, USA. years, these individuals exhibiting spontaneous Tel: +1 628 206 8188; e-mail: email@example.com control of HIV replication have been termed long- Curr Opin HIV AIDS 2022, 17:315–324 term nonprogressors, viremic controllers, or elite DOI:10.1097/COH.0000000000000748 controllers based on different virologic and clinical This is an open access article distributed under the Creative Commons criteria . Elite controllers, whose viral loads in the Attribution License 4.0 (CCBY), which permits unrestricted use, dis- plasma can remain undetectable for decades in the tribution, and reproduction in any medium, provided the original work is absence of ART, have a wide range of HIV reservoir properly cited. 1746-630X Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. www.co-hivandaids.com Controllers and natural cures In this review, we first discuss features of CD8 T KEY POINTS cells that are associated with and may contribute to þ spontaneous control of infection in elite controllers HIV antigen recognition is central to effective CD8 (Fig. 1) and consider how each of these features T-cell responses found in spontaneous controllers. might be leveraged to inform novel CD8 T-cell- HIV controllers have CD8 T-cell responses of enhanced based HIV remission strategies. Next, we discuss quality and localized in places where the HIV the importance of studying how the timing of reservoir persists. CD8 T-cell responses and the coordination Timing of responses and coordination with other between CD8 T cells and other immune responses immune cell types need to be considered for successful relates to HIV/SIV control both in acute infection strategies targeting CD8 T cells for HIV remission. and after treatment interruption. Finally, we discuss how this information might be used to successfully apply knowledge from HIV controllers to the design of novel therapies and clinical trials to induce cohorts of people who initially required ART to HIV remission. control viremia and were later found to suppress HIV replication after stopping ART have been I. HIV antigen recognition by CD8 T cells in identified and called posttreatment controllers elite controllers (PTCs; [7–9]), a phenotype that may be more frequent if ART is initiated early in the course Given the evidence that CD8 T cells play an impor- of infection. tant role in viral control in HIV infection, there has Evidence is strong that CD8 T cells can play a been intense investigation over the years into the critical role in mediating control of HIV in some question of whether specific epitope targeting and/ controllers. From studies in humans with HIV and or features of T-cell receptor (TCR) recognition of nonhuman primates (NHPs) with simian viruses viral peptides in natural infection favors viral con- (SIV, SHIV), potent CD8 T-cell responses have been trol. This concept has been supported by three major shown to associate with a lower viral load setpoint in lines of evidence: first, there is well documented both acute infection and after treatment interrup- association of elite controller status with protective tion [10–14]. In elite controllers, as we will discuss, class I HLA alleles; second, viral control has been the role of HIV-specific CD8 T-cell responses has associated with more cross-reactive ‘public’ TCRs been suggested by the association between viral (i.e., TCRs with CRD3 regions shared across different control and specific enrichment of class I human people); third, there is evidence that CD8 T cells or primate leukocyte antigen (HLA or Mamu) alleles from spontaneous controllers are more likely to and the development of potent HIV/SIV-specific target highly mutationally constrained – or ‘net- CD8 T-cell responses that are independent of the worked’ – epitopes. HLA/Mamu type [15–29]. More directly, depletion of CD8 T cells has been shown to lead to viral Human leukocyte antigen restriction rebound in NHPs that have either spontaneous elite Across the human population, polymorphisms control or viral suppression induced after treatment within the HLA locus provide one mechanism for in early infection with broadly neutralizing anti- genetically encoded inter-individual variation in bodies [30 ,31–33]. In contrast, waning antibody epitope targeting. As reviewed elsewhere [15,25], titers and sero-reversion suggest a fading humoral independent studies have identified strong associa- response in the rare exceptional elite controllers but, tions between specific class I HLA alleles and to date, no data have been reported on the CD8 T- increased likelihood of elite control (e.g., HLA- cell responses in these people. PTCs have so far not B 57, HLA-B 27, HLA-B 52 and HLA-B 14), although demonstrated the HLA genetic characteristics seen the presence of these alleles is neither necessary nor in elite controllers and early data suggest that they sufficient to predict controller status [17,19]. Spon- may have a low magnitude HIV-specific CD8 T-cell taneous control of HIV has been associated with response, at least as measured by interferon gamma specific polymorphisms in the amino acids lining production after HIV peptide stimulation . PTCs the HLA class I peptide-binding groove , which may have diverse mechanisms of control: some may have mechanisms attributed to natural killer (NK) likely influences the specific viral peptides that are cells for viral control but it is possible that, at least in presented to CD8 T cells in individuals with those some PTCs, CD8 T cells play a role in viral suppres- polymorphisms. While the population diversity of sion and that early treatment could also help to classical class I HLA alleles is vast, CD8 T cells can preserve CD8 T-cell function [34,35]. also be restricted by HLA-E, a nonclassical major 316 www.co-hivandaids.com Volume 17 Number 5 September 2022 R CD8 T-cell responses in HIV controllers Rutishauser and Trautmann þ þ FIGURE 1. Key CD8 T-cell features to target for HIV remission. HIV-specific CD8 T cells from elite controllers are more likely to be restricted by specific HLA types, target epitopes derived from the relatively evolutionarily conserved/constrained regions of the HIV genome, and to have broadly-reactive T cell receptors (TCRs) capable of recognizing variant epitopes. Evaluated directly ex vivo, they occupy a T cell memory-like differentiation state with high TCF-1 expression and low levels of expression of coinhibitory receptors such as PD-1 and they are more likely to accumulate in B cell follicles in lymphoid tissue (due to expression of CXCR5). After stimulation with HIV antigens in vitro, they demonstrate enhanced expansion capacity and an ability to generate secondary effector cells that have enhanced antiviral function. ‘Broadly reactive’ T-cell receptors histocompatibility complex (MHC) protein with In addition to favorable HLA alleles, people who only two alleles found in worldwide populations spontaneously control HIV are more likely to . Strikingly, cytomegalovirus (CMV)-vectored have HIV-specific CD8 T-cell responses consist- SIV vaccines can elicit broad HLA-E-restricted SIV- ing of TCRs with higher avidity and more cross- specific CD8 T cell responses that are associated reactive public clonotypes [41–43]. HLA alleles with the prevention of an established chronic infec- associated with HIV control promote thymic tion in 50% of animals upon viral challenge selection of more TCR repertoires that have [37,38]. HLA-E-restricted responses have been cross-reactivity for viral variants . Addition- detected in people with HIV but have not yet been ally, within the same HLA-B 27-restricted epitope associated with viral control [39 ,40]. Implications: response, controllers compared to progressors have distinct TCR clonotypes that are more HLA type should be characterized and accounted ‘broadly reactive,’ similar to the concept of for in the immunogenicity and efficacy analysis of broadly neutralizing antibodies in that they dem- all HIV remission studies. onstrate cross-reactivity to epitope variants T-cell-based remission strategies should aim to [42,45]. Cross-reactive TCRs have been shown elicit responses across diverse HLA types. to limit the ability of the virus to escape recog- Could targeting of HLA-E-restricted HIV-specific nition [46–48], but there is not a strict correlation CD8 T cells offer a more universal approach to between T cell clonotypic features and HIV therapeutic vaccination for HIV? 1746-630X Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. www.co-hivandaids.com 317 Controllers and natural cures control [49,50]. From a therapeutic standpoint, On the other end, narrowly targeting CD8 T-cell cross-reactive public TCRs identified from con- responses may be favorable to avoid epitope ‘dis- trollers could potentially be adapted for use in traction’ from the most conserved regions [64 ]. A adoptive T cell therapies (e.g., TCR-T cells; ). prophylactic vaccine strategy in NHPs targeting þ þ While HIV-specific CD8 T-cell responses with only three CD8 T-cell epitopes was sufficient to cross-reactive TCRs can be elicited after vaccina- maintain viral control after SIV challenge and tion in HIV-uninfected people , it is unclear viral escape from these three epitopes occurred whether therapeutic vaccines given to people concomitantly with loss of control of viral repli- with HIV with preexisting HIV-specific T cell cation . Similarly, viral escape of a single responses can overcome immunodominance pat- epitope has also been associated with loss of terns to elicit de novo responses or even to elicit long-term control in a person with HIV . new clonotypes and alter clonotype hierarchy These data suggest that a few well targeted epit- within preexisting responses . Implications: opes might be sufficient to induce viral control. Implications: How can broadly-reactive HIV-specific CD8þ T- cell responses be induced therapeutically, and Can therapeutic vaccines elicit CD8 T-cell can they contribute to posttreatment control responses that reliably recognize conserved/ of HIV? constrained regions across individuals with How can immune therapies induce novel diverse HLA types who are infected with diverse CD8þ T-cell responses during ART and over- HIV viral strains, and can these T cell responses come immunodominance of the existing T mediate durable control of HIV in vivo? cell responses? Should therapeutic vaccines aim to elicit broad or narrow responses to key epitopes? Are the considerations about breadth of epitope Epitope targeting targeting different for TCR-based adoptive T- Irrespective of the unmodifiable variable of HLA cell therapies? type, CD8 T cells from spontaneous HIV/SIV controllers may preferentially target epitopes that II. Quality and localization of HIV-specific are evolutionarily conserved and that have lower CD8 T-cell responses in elite controllers mutational tolerance (reviewed in ). Evidence Independent of T cell specificity and HLA type, for this phenomenon was first established when it HIV-specific CD8 T cells in elite controllers have was noted that the magnitude and breadth of also been shown to be highly functional, to HIV-specific CD8 T-cell responses specifically exhibit a more memory-like and less exhausted targeting the relatively conserved Gag structural differentiation state, and to localize better to sites protein but not the highly variable Env surface of reservoir persistence within lymph nodes com- protein epitopes (or the total HIV proteome) was pared to responses detected in people who do not associated with a lower viral load [13,14,54–56]. control HIV. In order to comprehensively evalu- At a finer epitope level, specific regions targeted ate different T cell-based HIV remission strategies, by elite controllers across HLA types infected with it will be critical to evaluate to what extent they clade B virus tend to be more conserved and have can promote each of these qualities. lower mutational tolerance (i.e., they are more evolutionarily constrained, or structurally ‘net- Enhanced expansion and antiviral worked’) than those in progressors . Con- functions served/constrained sequences (mostly derived from the Gag and Pol protein) have been used Compared to HIV-specific CD8 T cells from non- as therapeutic vaccine immunogens in several controllers (on or off ART), HIV-specific CD8 T approaches, although none has demonstrated cells from elite controllers have increased capacity clinical efficacy yet [57–62]. It not clear whether to produce multiple antiviral cytokines after pep- T cell-based therapeutic strategies for HIV are tide stimulation in vitro (polyfunctionality) and more likely to be successful if they target broad demonstrate increased expansion capacity, versus narrow epitope responses. As noted above, increased expression of the effector protein Per- spontaneous controllers appear to target broader forin, and sustained killing of infected target cells responses within conserved regions compared to over the course of several days of peptide stim- noncontrollers. Furthermore, epitope breadth eli- ulation in vitro [67–77]. It is unclear whether this cited by a therapeutic vaccine has been shown to enhanced functional capacity compared to the associate with delay to viral rebound in NHPs . functionally exhausted cells in noncontrollers is 318 www.co-hivandaids.com Volume 17 Number 5 September 2022 R CD8 T-cell responses in HIV controllers Rutishauser and Trautmann acquired as a consequence of elite controllers cells are associated with viral control in SIV- likely having a shorter duration and lower cumu- infected NHPs . Taken together, these data lative exposure to high viral load prior to viral suggest that while HIV-specific CD8 T cells in the suppression compared to noncontrollers, or lymph nodes from controllers may have a less whether this capacity is directly responsible for effector differentiated phenotype compared to mediating and maintaining durable viral suppres- cells found in the blood, they nonetheless possess sion. Indeed, people or NHPs who experience the capacity to expand and differentiate into curtailed viremia due to initiation of ART early potent antiviral effector cells and traffic to B cell in the course of infection also have more highly follicles where the HIV reservoir persists. Several functional HIV-specific CD8 T cells (, and immune-based remission strategies are being unpublished data, L.T.). Regardless, the func- developed to re-direct CD8 T cells to the B cell tional properties of HIV-specific CD8 T cells in follicles, including pharmacologic treatment with elite controllers serve as a model for the type of IL-15 agonists, genetically engineering CXCR5- þ þ CD8 T-cell response that should ideally be eli- expressing CD8 T cells for adoptive transfer, cited in remission strategies. Indeed, recent stud- and the development of bi-specific antibodies ies have shown that T cell function and expansion to redirect follicular CD8 T cells to kill infected can be enhanced by promoting cellular pathways cells [103,104,105 ,106,107]. Implications: that are active in HIV-specific CD8 T cells from elite controllers or inhibiting those found in non- How can remission strategies be tailored to controllers (e.g., via inhibition of co-inhibitory optimize the generation of HIV-specific CD8 T receptor signaling, apoptosis pathways, the mam- cells that migrate to lymphoid tissues/B cell malian target of rapamycin (mTOR) pathway, follicles and have the potential to generate a and/or overexpression of TCF-1, a Wnt signaling potent effector response ‘at the right place at transcription factor that promotes memory T cell- the right time’? && & & like expansion capacity; [79 ,80–82,83 ,84 ]). Implications: III. Timing of CD8 T-cell responses and How can therapeutic strategies for HIV remis- coordination with other immune responses sion promote the generation of nonexhausted While HIV-specific CD8 T cells have been exten- HIV-specific CD8 T cells with functional prop- sively studied in spontaneous controllers during erties similar to elite controllers (i.e., enhanced the phase of long-term control, there are very expansion capacity and antiviral function)? limited data on CD8 T-cell dynamics during acute infection in people destined to become Tissue localization controllers. Specifically, it is unclear whether or how the features of HIV antigen recognition and To control viral replication, HIV-specific CD8 T HIV-specific CD8 T-cell quality and localization cells need to be localized in close proximity to discussed in the two previous sections directly sites of viral reservoir persistence in tissues. HIV contribute to control early in primary infection persists in lymphoid tissues throughout the body or whether they arise as a consequence of these with a high burden of infected CD4 T cells found individuals achieving greater viral control. in the gastrointestinal tract [85,86]. Increased Understanding the timing and nature of the frequencies of functional HIV-specific CD8 T CD8 T-cell response in early HIV/SIV infection cells have been observed in the rectal mucosa of in spontaneous controllers, how CD8 T cells HIV controllers . Within lymphoid tissue, engage rebounding virus in posttreatment con- several studies in humans and NHPs have shown trollers, and how CD8 T-cell responses coordi- that HIV/SIV preferentially persists in both con- nate with other immune responses to trollers and noncontrollers in follicular helper productively engage with and suppress the virus CD4 T cells localized within B cell follicles, from at the time of viral intercept in both settings is which HIV-specific CD8 T cells are mostly therefore crucial to directly inform the develop- excluded [33,88–97]. While it has been suggested ment of improved remission strategies. that the HIV-specific CD8 T cells located in lym- phoid tissue may have impaired cytolytic func- Timing of CD8 T-cell responses tion , these cells (or at least a subset of them) may be poised to respond rapidly to antigen While current data are limited, studying immune stimulation [99–101]. Moreover, highly func- responses that occur in acute infection or imme- tional CXCR5-expressing SIV-specific CD8 T diately post-ART in HIV controllers may identify 1746-630X Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. www.co-hivandaids.com 319 Controllers and natural cures FIGURE 2. CD8 T-cell characteristics of viral control: Potential implications for HIV remission strategies. (a) List of implication for novel HIV remission strategies and remaining questions to be answered. (b) HIV controllers grouped and analyzed for the different CD8 T-cell characteristics associated with viral control will inform HIV remission strategies and need to be targeted in combination with other factors contributing to viral control. targets for therapeutic intervention to promote These data suggest that CD8 T-cell responses HIV remission. In the SIV model, while CD8 T may have a role early in infection in some sponta- cells generally exhibit a suboptimal ability to neous controllers, but the exact timing of these suppress SIV in acute infection, in controller mac- responses and their impact on control is not yet aques, suppressive capacity increases progres- fully clear. In noncontrollers in the absence of any sively before the establishment of sustained immunologic intervention, two studies have sug- low-level viremia . In humans, a study gested that HIV/SIV-specific CD8 T cells do not reported higher frequencies of proliferating respond early enough after ART discontinuation CD8 T cells in acute infection in two individuals to prevent viral rebound and only exert an effect who maintained low viremia without ART, sug- on viral load set-point after viral rebound þ þ gesting that CD8 T cells might play an early role [112,113]. However, the HIV-specific CD8 T-cell in viral control . Recently, three cases of response right after ART is stopped has not yet women identified in early infection who subse- been described in controllers. Implications: quently developed spontaneous control in the absence of ART were described, with two showing Studies describing the earliest interactions between þ þ robust and one very limited HIV-specific CD8 T- the emerging virus and the CD8 T-cell response in cell responses during acute infection [110,111]. both spontaneous and posttreatment controllers 320 www.co-hivandaids.com Volume 17 Number 5 September 2022 R CD8 T-cell responses in HIV controllers Rutishauser and Trautmann reactive’ TCRs that target highly conserved/ willbekeytoinformingthesuccessfuldevelopment evolutionarilyconstrained regions of the virus, of interventions aimed at priming an immune arelocalizedtositesofreservoirpersistence,are response to target the early viral intercept. durable and highly functional, and are capable of responding rapidly(either on theirownorin Coordination of immune responses post- conjunction with other immune responses) to antiretroviral therapy emerging virus after ART is discontinued. The studies described in the section above suggest (2) Studies that include HIV remission interven- that, in the majority of people with HIV who fail to tions that target CD8 T cells should ideally control the virus in the absence of ART, CD8 Tcells report HLA typing of study participants, clin- mayrespondtooslowlytostopviralspreadafterART ical information about pre-ART viral loads and is discontinued. Effective immunity during the early duration of infection prior to ART initiation, stages of viral spread likely requires other interven- epitope mapping and evaluation for broadly tions to reduce the size of the HIV reservoir, and/or to reactive TCRs, analysis of the long-term dura- augment other immune responses to either directly bility and functional capacity (including promote functional CD8 T-cell responses or to con- expansion capacity and, ideally, viral inhibi- tain early viral replication and thus allow CD8 T tion), and lymphoid tissue localization or at cells time to expand and mature (reviewed in ). least homing potential (e.g., CXCR5 expres- For example, type I interferon-producing plasmacy- sion) of the CD8 T-cell response. toid dendritic cells (pDCs) provide help to CD8 T (3) As a field, we need to better understand how cells and have recently been shown to sense the virus the timing of the CD8 T-cell response and its intissuesandbecomeactivatedpriortoviralrebound coordination with other immune responses detectable in the blood . Classical dendritic cells in blood and tissues at the time of viral inter- that are capable of priming CD8 T cells have addi- cept relates to viral control in natural infec- tionally been shown to be highly functional in spon- tion and after therapeutic intervention. taneous controllers . Antibodies have also been (4) As different CD8 T-cell characteristics asso- suggested as enabling immune complexes promot- ciated with viral control are likely shared by ing stronger CD8 T-cell responses . Under- the different groups of controllers in natural standing the interaction between CD8 Tcells and infection, but may differ by individual, it is other cell types and immune responses – such as also important to recognize that HIV remis- pDCs, other innate immune cells, CD4 Tcells, orB sion strategies might need to be tailored to cells/antibodies – will likely be required to fully different groups of individuals depending on understand this early response during viral rebound the mechanism targeted (Fig. 2b). In addition, post-ART. Implications: combination therapies might be necessary as interventions focusing only on CD8 T cells Combined interventions targeting multiple might not be sufficient to induce viral control virologic and immunologic mechanisms will . likely be required to achieve HIV remission. Interventions that allow for a transient reduction Acknowledgements of viral replication post-ART could allow for a better maturation of the CD8 T-cell response We would like to thank Julie Mitchell for her help in in response to rebounding virus and give it designing Fig. 2 and Steven Deeks for comments on the enough time to start controlling viral replication. text. Figs. 1 and 2 were designed using Biorender. The opinions or assertions contained herein are the private views of the authors, and are not to be construed as official, or as reflecting true views of the National CONCLUSION Institutes of Health. The past three decades of studies on CD8 T-cell responses in spontaneous HIV/SIV controllers Financial support and sponsorship have provided important information on their This publication was made possible with support key role and potential mechanisms contributing from NIH grants UM1AI164560 (R.R., L.T.), to viral suppression. In order to successfully apply R01AI147749 (L.T.), K23AI134327 (R.R.), this knowledge to T cell-based remission strat- R01AI170239 (R.R.). egies, we suggest the following (Fig. 2a): Conflicts of interest (1) CD8 T-cell-based remission strategies should seek to elicit T cell responses with ‘broadly There are no conflicts of interest. 1746-630X Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. www.co-hivandaids.com 321 Controllers and natural cures 24. Yant LJ, Friedrich TC, Johnson RC, et al. the high-frequency major REFERENCES AND RECOMMENDED histocompatibility complex (MHC) class I allele Mamu-B17 Is asso- READING ciated with control of simian immunodeﬁciency virus SIVmac239 replica- Papers of particular interest, published within the annual period of review, tion. J Virol 2006; 80:6720–16720. have been highlighted as: 25. Collins DR, Gaiha GD, Walker BD. CD8þ T cells in HIV control, cure and of special interest prevention. 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Current Opinion in HIV and AIDS – Wolters Kluwer Health
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