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. Author manuscript; available in PMC: 2017 Jul 1.
Published in final edited form as: Curr Opin HIV AIDS. 2016 Jul;11(4):409–416. doi: 10.1097/COH.0000000000000286

Kill: Boosting HIV-specific immune responses

Lydie Trautmann 1
PMCID: PMC5098478  NIHMSID: NIHMS795037  PMID: 27054280

Abstract

Purpose of review

Increasing evidences suggest that purging the latent HIV reservoir in virally-suppressed individuals will require both the induction of viral replication from its latent state and the elimination of these reactivated HIV infected cells (“Shock and Kill” strategy). Boosting potent HIV-specific CD8 T cells is a promising way to achieve an HIV cure.

Recent findings

Recent studies provided the rationale for developing immune interventions to increase the numbers, function and location of HIV-specific CD8 T cells to purge HIV reservoirs. Multiple approaches are being evaluated including very early suppression of HIV replication in acute infection, adoptive cell transfer, therapeutic vaccination or use of immunomodulatory molecules. New assays to measure the killing and antiviral function of induced HIV-specific CD8 T cells have been developed to assess the efficacy of these new approaches. The strategies combining HIV reactivation and immunobased therapies to boost HIV-specific CD8 T cells can be tested in in vivo and in silico models to accelerate the design of new clinical trials.

Summary

New immunobased strategies are explored to boost HIV-specific CD8 T cells able to purge the HIV-infected cells with the ultimate goal of achieving spontaneous control of viral replication without antiretroviral treatment.

Keywords: HIV-specific CD8 T cells, immunobased therapies, post-treatment control of HIV replication

Introduction

Despite the success of antiretroviral therapy (ART) in controlling HIV replication, ART does not eradicate HIV and does not optimally reconstitute the immune system (1, 2). Novel immunobased therapies that would induce the immune-mediated control of HIV replication in the absence of ART or the eradication of the HIV reservoir are needed. To date, a single case of HIV cure and rare cases of transient remission have been reported (3–8). Other few reported cases of long-term remission in individuals controlling viral replication after ART interruption, also called “post-treatment controllers”, have been documented (9–13). However for most HIV-infected individuals, HIV viral load rebounds at a median time of 14 days after treatment interruption from a large number of HIV variants (14–16). Inducing HIV expression has been proposed as a strategy to eliminate persistently HIV-infected cells that constitute the viral reservoir (17–19). Latency reversing agents (LRAs) with potential for viral induction have been identified in in vitro models of HIV latency (20, 21) and are discussed in reviews on “shock” strategies in this issue. Despite their ability to induce HIV production, LRAs did not induce measurable decrease of the HIV reservoir size in vivo (22–25). Therefore, purging these latent HIV reservoirs remaining under ART will need in addition to the induction of viral expression (Shock), the elimination of these reactivated latently-infected cells by either direct cytolytic targeting or by immunotherapeutic intervention (Kill) (26). Whereas rapid progress is made on the discovery and characterization of new LRAs to reactivate the latent HIV reservoir, the critical issue of how to kill the reactivated cells has still to be defined. In this review, the recent advances in using HIV-specific CD8 T cells to purge the latent HIV reservoir and achieve viral control after ART interruption will be discussed.

The need for efficient HIV-specific CD8 T cells to purge the HIV reservoir

Several observations suggest that HIV-specific CD8 T cells are important for the control of HIV replication by killing the productively HIV-infected CD4 T cells including the generation and maintenance of viral escape mutations in CD8 T cell epitopes or the superior control of viral replication by certain HIV-specific clonotypes restricted by HLA-B57 and B27 in elite controllers (27–29). The critical role of CD8 T cells in controlling HIV reservoir in virally-suppressed conditions has been demonstrated in the SIV model, where CD8 T cell depletion led to a rapid increase in viremia in elite controller macaques (30, 31) but also in virally suppressed ART-treated macaques (32). In both cases, the recovery of CD8 T cells after depletion was associated with a reduction of viral production. However, HIV-specific CD8 T cell mediated control of HIV replication is not sufficient to purge the HIV reservoir and prevent viral load rebound after ART interruption. Several parameters contribute to the lack of viral reservoir clearance by HIV-specific CD8 T cells. Prior to ART, many studies have shown that HIV-specific CD8 T cells are dysfunctional and have characterized the mechanisms of this dysfunction (33–36). After ART initiation, these defects are not fully restored and the remaining number of HIV-specific CD8 T cells is extremely low due to the sharp decrease of antigen load and continues to decay over time (37–42). Additionally, viral escape in epitopes targeted by CD8 T cells emerging rapidly early in infection as well as viral mechanisms interfering with the presentation of viral antigens prevent CD8 T cells to recognize efficiently HIV-infected cells. Lastly, the compartmentalization of HIV-infected cells in B cell follicles hardly accessible to HIV-specific CD8 T cells adds another barrier to efficient killing of these cells (31, 43, 44). The low frequency of HIV-specific CD8 T cells, their partial dysfunction and their location outside of HIV reservoir sanctuaries may account for the failure of previous eradication strategies that have been implemented in HIV-infected individuals who have been receiving ART for years.

Recent studies suggested that HIV-specific CD8 T cell could play an important role in purging HIV reservoirs. Shan and colleagues reported that after in vitro expansion of HIV-specific CD8 T cells from ART-treated subjects, these cells were able to eliminate reactivated HIV-infected CD4 T cells in an in vitro model of latency (45). Hansen and colleagues developed a new RhesusCMV vaccine that induced high frequencies of potent SIV-specific CD8 T cells leading to viral control and complete elimination of SIV reservoirs in half of the vaccinated macaques (46, 47). The high frequencies of SIV-specific CD8 T cells induced by this therapeutic vaccine were directed against broad non-classical epitopes restricted by HLA-E suggesting that immunobased strategies boosting HIV-specific CD8 T cells need to induce more efficient responses than the ones occurring in natural infection (48, 49). CD8 T cell responses restricted by HLA-E have been documented in infectious diseases, cancer and autoimmunity but have been mostly characterized as regulatory responses (50–52). Whether HIV-specific CD8 T cells responses against HLA-E restricted epitopes will be defined as important in controlling HIV replication and can be induced in human is still unknown but is under investigation. These studies provided the rationale for new therapeutic strategies that combine agents that reactivate latently-infected CD4 T cells with immune interventions that increase the numbers, function and location of HIV-specific CD8 T cells to clear HIV reservoirs in individuals on ART, with the ultimate goal of achieving spontaneous control of viral replication without treatment (53).

Strategies to boost HIV-specific CD8 T cell responses in ART-treated subjects

Different approaches are currently tested to boost HIV-specific CD8 T cells in ART-treated individuals and are described below.

1- Initiating ART in acute infection

Although the latent HIV reservoir is seeded very early in infection (54, 55), initiating ART as early as possible can limit the size of the viral reservoir and could also preserve the quality of HIV-specific responses (56–63). Whether a preserved immunity could lead to the control of viral replication after treatment cessation remains largely unknown but two studies initiated ART in primary infection and assessed the viral rebound after ART discontinuation. In the SPARTAC study, treatment initiation within 6 months of infection resulted in a delay in viral rebound after ART cessation (64, 65). Hurst and colleagues reported recently that immune checkpoint blockers PD-1, Tim-3 and Lag-3 measured prior to ART initiation strongly predicted time to viral rebound after ART cessation (66). In the VISCONTI cohort, treatment was initiated within the first 3 months of infection and kept for a median of 7 years before ART cessation; fourteen post-treatment controllers were observed in that cohort (11). These two studies suggest that timely ART initiation may pave the way for a better viral control after ART cessation but the mechanism of viral control in post-treatment controller still needs to be identified (67). Early in infection, HIV-specific CD8 T cells can contribute to control viremia (68–71) but become rapidly dysfunctional after peak viremia due to sustained hyperactivation and change in their metabolism (72). Therefore, initiating ART in the earliest stage of acute infection before peak viremia is reached might be necessary to achieve HIV remission due to initiating ART early in infection. This will be answered in ongoing or planned clinical studies.

2- Adoptive transfer of ex vivo expanded HIV-specific CD8 T cells

Early studies in the SIV model described adoptive transfer of CD8 T cells in acute and chronic untreated infection with limited impact on viral replication (73–75). However the impact of adoptive SIV-specific CD8 T cell transfer on the SIV reservoir under suppressed viremia before treatment interruption remains to be tested. Recently, Sung and colleagues demonstrated that ex vivo expanded CD8 T cells derived from ART-treated HIV-infected individuals controlled the autologous viral reservoir better than bulk CD8 T cells, supporting the use of adoptive CD8 T cell transfer for purging the HIV reservoir in vivo 76). Emerging findings from adoptive CD8 T cell transfer approaches tested in cancer both in mouse studies and clinical trials show promising results and indicate that intrinsic properties related to the differentiation state of the adoptively transferred CD8 T cells are crucial for the success of these approaches (77). Chapuis and colleagues demonstrated that HIV-specific CD8 T cells expanded in vitro from the central memory pool of ART-treated individuals were detected more than 84 days in vivo after re-injection (78). However, the mechanisms that underlie successful adoptive CD8 T cell transfer in HIV-infected ART-treated individuals remain unknown and the most effective T cell populations to kill HIV reservoir cells in vivo have yet to be identified.

3- Therapeutic vaccines

Over the last decade, many T cell based vaccine regimen have been tested to boost CD8 T cell responses (reviewed in (79)). Live attenuated vectors have been favored as they induce robust CD8 T cell responses but other vaccination strategies using peptides, proteins, or dendritic cells have been tested in HIV-infected individuals on ART. These therapeutic vaccines tested showed limited success in delaying viral rebound after cessation of ART but lessons can be learned from these therapeutic vaccination studies (reviewed in (80)) and new therapeutic vaccines show promising results (reviewed in (81)). One of the reasons for the limited success of therapeutic vaccines tested in clinical trials so far might be that these interventions have been designed following classical vaccine regimen for inducing memory T cells. The boosting of HIV-specific CD8 T cells through therapeutic vaccination should aim at inducing numerous, potent, broad effector CD8 T cells (82). Defining the correlates of vaccine efficacy for achieving HIV remission after treatment interruption would help guiding the development of successful therapeutic vaccines.

4- Immunomodulators

Immunomodulation strategies aim at potentiating HIV-specific CD8 T cells either endogenous or induced by vaccines to kill reactivated HIV-infected cells. Some of the strategies currently tested ex vivo and in clinical trials to reactivate HIV from latently-infected CD4 T cells target signaling pathways associated with T cell activation and homeostasis, including PKC activators, as Bryostatin or Ingenol, and cytokines, as IL-7 (83, 84). Besides their effect on the latent HIV reservoir, these molecules could also influence differentially the activation and function of HIV-specific CD8 T cell responses stimulated contemporaneously. Vaccine adjuvants can also play a dual role of reactivating the latent reservoir and enhancing vaccine responses. Agonist molecules targeting TLR7 and TLR9 have been shown to reactivate the HIV reservoir (85, 86). Finally, the success of monoclonal antibodies targeting immune checkpoint blockers in cancer treatment could be transposed to HIV eradication. A recent clinical trial blocking the PD-1/PD-L1 pathway in ART-suppressed individuals suggested that this treatment could revert the immune exhaustion of HIV-specific CD8 T cells while enhancing HIV expression in CD4 T cells (87).

Although some of these different strategies explored to boost HIV-specific CD8 T cells would not be applicable to all HIV-infected individuals, they are critical in defining the characteristics of efficient HIV-specific CD8 T cells that could control viral rebound after ART cessation and will guide the development of novel therapeutic approaches.

Assays to measure the number, location and killing capacity of HIV-specific CD8 T cells

The different approaches currently tested to boost HIV-specific CD8 T cells in ART-treated individuals described above will require specific assessments of the CD8 T cells induced: their number; but also their ability to persist in vivo; the location of these cells in particular in sanctuary sites of viral persistence; and their capacity to kill reactivated latently-infected CD4 T cells.

1- Quantify the numbers and maintenance of HIV-specific CD8 T cells during immune intervention and ART interruption

The frequencies of HIV-specific CD8 T cells are very low in the peripheral blood of ART-treated individuals and are difficult to detect using standard assays such as ELISPOT or ex vivo ICS. Furthermore, the repeated sampling of subjects undergoing immune intervention and analytical treatment interruption limits the number of cells available to analyze these low frequencies. The same limitations exist for the measurement of HIV reservoir under ART and have led to the development of ultrasensitive methods for viral detection. Similarly, ultrasensitive methods to detect HIV-specific CD8 T cells accurately under ART should be developed and validated.

2- Assess the location of HIV-specific CD8 T cells

Immunohistochemistry allows the visualization of T cell localization in tissues. The detection of CD8 T cells in paraffin embedded tissues is not optimal yet but will be necessary to localize the CD8 T cells in mucosal tissues or secondary lymphoid organs. The detection of HIV-specific CD8 T cells in tissues can be done by in situ tetramer staining (88), a powerful but difficult method that might not be widely available in many laboratories and requires the staining of tissues from individuals having HLA alleles matching available tetramers. Alternatively, defining markers on HIV-specific CD8 T cells that are representative of the CD8 cells location in specific tissues and can be measured on dissociated tissues by flow cytometry would facilitate the assessment of HIV-specific CD8 T cell localization in tissues.

3- Measure the killing capacity of HIV-specific CD8 T cells

The cytolytic activity is the major function of CD8 T cells required for the elimination of HIV-infected cells but is still rarely evaluated, as assays used for this purpose are cumbersome, cell consuming and have been difficult to standardize. Accurate measurement of this function is of paramount importance when characterizing effector functions of CD8 T cells, as no reliable predictors of effective cell-mediated cytotoxicity have been described yet (89, 90). Using a new assay to quantify the intrinsic killing capacity of HIV-specific CD8 T cells, we have observed that HIV-specific CD8 T cells in primary infection exhibit a significantly higher cytotoxic capacity than HIV-specific CD8 T cells in chronic infection (72, 91, 92). A new assay measuring the antiviral activity of CD8 T cells has been recently developed using in vitro infected CD4 T cells co-cultured with CD8 T cells (45, 93–95). Using this assay, Yang et al. demonstrated a significant association between CD8 T cell viral inhibition activity in vitro and the rate of CD4 T cell loss in early HIV-1 infection as well as the rate of CD4 T cell decline in chronically infected individuals (96). Whether this viral inhibition is mediated by direct cytolytic activity of CD8 T cells is still unknown and other assays that can recapitulate the killing of primary latently-infected CD4 T cells from ART-treated individuals by HIV-specific CD8 T cells need to be developed.

New assays requiring limited PBMCs that measure small frequencies of HIV-specific CD8 T cells while assessing their quality, location and ability to kill HIV-infected cells would be an important platform to test the immune intervention strategies for HIV reservoir eradication in ART-treated individuals.

In vivo and in silico models to test therapeutic immune interventions

New immune interventions will be tested in clinical trials in the coming years using combination strategies to reactivate HIV reservoir and boost HIV-specific CD8 T cells in order to eradicate HIV. In designing these new therapies combining multiple components, it will be critical to understand the effect of the drugs used for HIV reactivation on HIV-specific CD8 T cells and to determine the timing of administration of these therapies. Indeed, current LRAs have been shown to inhibit HIV-specific CD8 T cell responses in vitro 97), so the timing of administration of these LRAs and vaccine regimen needs to be carefully chosen to avoid these deleterious effects on CD8 T cells. In vivo effects of the different combinations of LRAs and immunobased interventions will be difficult to predict and calls for models to anticipate the outcome and accelerate the testing of combination strategies. In the recent years, the antiretroviral regimens have been optimized in SIV-infected macaques and allow for viral suppression (see review on “animal models for eradication strategies” in this issue). Therefore, the non-human primate model can be used for testing of new vaccine regimen or immune intervention and drug combinations. This model also allows for a deeper examination of HIV reservoirs and HIV-specific CD8 T cells in tissues that would not be accessible in human.

In addition, mathematical modeling is essential to inform novel combination strategies. In silico models have provided accurate and useful information on viral dynamics (98–101) and have already been used to model post-treatment control. A recent study modeled the dynamics between viral reactivation and control by the immune response after ART interruption and predicted the time to relapse in individuals treated in primary infection (102). Smith and colleagues used in vivo, in vitro and in silico data to model the control of viral rebound by CD8 T cells post-transplantation in an HIV autologous elite controller that underwent stem cell transplantation (103). In another study, based on previous clinical trial with analytical treatment interruption, Pinkevych and colleagues estimated the rate of successful reactivation after ART cessation to be once every 3.6 days (104). For the immune response to HIV, even though data are available on the in vivo killing rate of infected cells by CD8 T cells (105), few in silico models are available to predict the number and nature of CD8 T cells required for HIV remission. However, a recent study modeled the timing of LRA administration and suggested that reactivation of the latent reservoir could be more effective at start of ART rather than on long term ART, when HIV-specific CD8 T cells are still present in high numbers (106). The use of combination strategies will introduce more variables and increase considerably the complexity of these models. Data from clinical trials including analytical treatment interruption will help building and refining the mathematical models of post-treatment control, which will then guide the next trials. This iterative process should accelerate the pace of testing successful immune interventions to eradicate HIV.

Conclusion

Despite major advances in defining the mechanisms of HIV latency and its reactivation using different strategies (107, 108), the “Kill” part of the “Shock and Kill” strategy has to be defined in the clinical setting. Evidences from the RhCMV vaccine and in vitro data show that superior HIV-specific CD8 T cells need to be induced by immune intervention in order to eradicate HIV infected cells. Several strategies are tested to boost these responses but whether HIV-specific CD8 T cells need to be boosted numerically and/or qualitatively and to which extent are still open questions. Numerous trials will be performed in the next few years and new assays measuring the quality and effector function of the HIV-specific CD8 T cells induced will be important to evaluate these interventions. In vivo and in silico models for testing novel combination strategies aiming at reactivating the HIV reservoir and boosting HIV-specific CD8 T cells will accelerate the pace of human clinical trials. In all these immunobased strategies, timing of intervention might play an important role in the outcome and should be carefully assessed. It is possible that potent immune interventions to boost HIV-specific CD8 T cells would also induce HIV reactivation and would be sufficient to eliminate HIV reservoirs (109, 110). In that case, a “Purge” strategy aiming at the elimination of HIV-infected cells by boosting HIV-specific CD8 T cell killing could lead to HIV eradication. Finally, defining immunological predictors of post-treatment control will be critical to guide the development of immune-based therapies to achieve HIV remission after ART cessation.

Key points.

  • Recent studies provide the rational to develop strategies to boost HIV-specific CD8 T cells to achieve an HIV cure.

  • Boosting HIV-specific CD8 T cells could be achieved by early ART initiation, adoptive cell transfer, therapeutic vaccination and immunoregulatory interventions.

  • New immunological assays to assess the number, quality and effector functions of HIV-specific CD8 T cells should be used to assess immune-based therapies.

  • In vivo and in silico models can guide the development of combinations strategies to boost HIV-specific CD8 T cells in combination with intervention to reactivate the latent HIV reservoir.

Acknowledgments

Financial support and sponsorship

This work was supported by the following sources: NIH grant R01AI108433, R21AI116233 and a cooperative agreement (W81XWH-07-2-0067) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. Department of Defense (DoD). The views expressed are those of the authors and should not be construed to represent the positions of the U.S. Army or the Department of Defense.

Footnotes

Conflicts of interest

The author declares no conflict of interest.

References

  • 1.Corbeau P, Reynes J. Immune reconstitution under antiretroviral therapy: the new challenge in HIV-1 infection. Blood. 2011;117(21):5582–5590. doi: 10.1182/blood-2010-12-322453. [DOI] [PubMed] [Google Scholar]
  • 2.Hunt PW. HIV and inflammation: mechanisms and consequences. Current HIV/AIDS reports. 2012;9(2):139–147. doi: 10.1007/s11904-012-0118-8. [DOI] [PubMed] [Google Scholar]
  • 3.Hutter G, Nowak D, Mossner M, Ganepola S, Mussig A, Allers K, et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med. 2009;360(7):692–698. doi: 10.1056/NEJMoa0802905. [DOI] [PubMed] [Google Scholar]
  • 4.Henrich TJ, Hu Z, Li JZ, Sciaranghella G, Busch MP, Keating SM, et al. Long-term reduction in peripheral blood HIV type 1 reservoirs following reduced-intensity conditioning allogeneic stem cell transplantation. J Infect Dis. 2013;207(11):1694–1702. doi: 10.1093/infdis/jit086. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Henrich TJ, Hanhauser E, Marty FM, Sirignano MN, Keating S, Lee TH, et al. Antiretroviral-free HIV-1 remission and viral rebound after allogeneic stem cell transplantation: report of 2 cases. Annals of internal medicine. 2014;161(5):319–327. doi: 10.7326/M14-1027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Persaud D, Gay H, Ziemniak C, Chen YH, Piatak M, Jr, Chun TW, et al. Absence of detectable HIV-1 viremia after treatment cessation in an infant. N Engl J Med. 2013;369(19):1828–1835. doi: 10.1056/NEJMoa1302976. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Luzuriaga K, Gay H, Ziemniak C, Sanborn KB, Somasundaran M, Rainwater-Lovett K, et al. Viremic relapse after HIV-1 remission in a perinatally infected child. N Engl J Med. 2015;372(8):786–788. doi: 10.1056/NEJMc1413931. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Butler KM, Gavin P, Coughlan S, Rochford A, Mc Donagh S, Cunningham O, et al. Rapid viral rebound after 4 years of suppressive therapy in a seronegative HIV-1 infected infant treated from birth. The Pediatric infectious disease journal. 2015;34(3):48–51. doi: 10.1097/INF.0000000000000570. [DOI] [PubMed] [Google Scholar]
  • 9.Hocqueloux L, Prazuck T, Avettand-Fenoel V, Lafeuillade A, Cardon B, Viard JP, et al. Long-term immunovirologic control following antiretroviral therapy interruption in patients treated at the time of primary HIV-1 infection. Aids. 2010;24(10):1598–1601. doi: 10.1097/qad.0b013e32833b61ba. [DOI] [PubMed] [Google Scholar]
  • 10.Lodi S, Meyer L, Kelleher AD, Rosinska M, Ghosn J, Sannes M, et al. Immunovirologic control 24 months after interruption of antiretroviral therapy initiated close to HIV seroconversion. Archives of internal medicine. 2012;172(16):1252–1255. doi: 10.1001/archinternmed.2012.2719. [DOI] [PubMed] [Google Scholar]
  • 11.Saez-Cirion A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, Girault I, Lecuroux C, et al. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS Pathog. 2013;9(3):e1003211. doi: 10.1371/journal.ppat.1003211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Frange P, Faye A, Avettand-Fenoel V, Bellaton E, Descamps D, Angin M, et al. HIV-1 virological remission lasting more than 12 years after interruption of early antiretroviral therapy in a perinatally infected teenager enrolled in the French ANRS EPF-CO10 paediatric cohort: a case report. Lancet HIV. 2016;3(1):49–54. doi: 10.1016/S2352-3018(15)00232-5. [DOI] [PubMed] [Google Scholar]
  • 13.Gossez M, Ramjee G, Hurst J, Kaleebu P, Rees H, Porter K, et al. Virological Remission After ART Interruption in African HIV-1 Seroconverters. CROI2016, Boston. 2016 Abstract 87. [Google Scholar]
  • 14.Ruiz L, Martinez-Picado J, Romeu J, Paredes R, Zayat MK, Marfil S, et al. Structured treatment interruption in chronically HIV-1 infected patients after long-term viral suppression. Aids. 2000;14(4):397–403. doi: 10.1097/00002030-200003100-00013. [DOI] [PubMed] [Google Scholar]
  • 15. Rothenberger MK, Keele BF, Wietgrefe SW, Fletcher CV, Beilman GJ, Chipman JG, et al. Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption. Proc Natl Acad Sci U S A. 2015;112(10):1126–1134. doi: 10.1073/pnas.1414926112. Reports that HIV variants replicate in multiple locations in lymphatic tissues after ART interruption.
  • 16.Calin R, Hamimi C, Lambert-Niclot S, Carcelain G, Bellet J, Assoumou L, et al. Treatment interruption in chronically HIV-infected patients with an ultralow HIV reservoir. Aids. 2016;30(5):761–769. doi: 10.1097/QAD.0000000000000987. [DOI] [PubMed] [Google Scholar]
  • 17.Lehrman G, Hogue IB, Palmer S, Jennings C, Spina CA, Wiegand A, et al. Depletion of latent HIV-1 infection in vivo: a proof-of-concept study. Lancet. 2005;366(9485):549–555. doi: 10.1016/S0140-6736(05)67098-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Richman DD, Margolis DM, Delaney M, Greene WC, Hazuda D, Pomerantz RJ. The challenge of finding a cure for HIV infection. Science. 2009;323(5919):1304–1307. doi: 10.1126/science.1165706. [DOI] [PubMed] [Google Scholar]
  • 19.Autran B. Toward a cure for HIV-Seeking effective therapeutic vaccine strategies. Eur J Immunol. 2015;45(12):3215–3221. doi: 10.1002/eji.201545513. [DOI] [PubMed] [Google Scholar]
  • 20.Bullen CK, Laird GM, Durand CM, Siliciano JD, Siliciano RF. New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo. Nat Med. 2014;20(4):425–429. doi: 10.1038/nm.3489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Martins LJ, Bonczkowski P, Spivak AM, De Spiegelaere W, Novis CL, DePaula-Silva AB, et al. Modeling HIV-1 Latency in Primary T Cells Using a Replication-Competent Virus. AIDS Res Hum Retroviruses. 2016;32(2):187–193. doi: 10.1089/aid.2015.0106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Archin NM, Liberty AL, Kashuba AD, Choudhary SK, Kuruc JD, Crooks AM, et al. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature. 2012;487(7408):482–485. doi: 10.1038/nature11286. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Blazkova J, Chun TW, Belay BW, Murray D, Justement JS, Funk EK, et al. Effect of histone deacetylase inhibitors on HIV production in latently infected, resting CD4(+) T cells from infected individuals receiving effective antiretroviral therapy. J Infect Dis. 2012;206(5):765–769. doi: 10.1093/infdis/jis412. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Bartholomeeusen K, Fujinaga K, Xiang Y, Peterlin BM. Histone deacetylase inhibitors (HDACis) that release the positive transcription elongation factor b (P-TEFb) from its inhibitory complex also activate HIV transcription. J Biol Chem. 2013;288(20):14400–14407. doi: 10.1074/jbc.M113.464834. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Sogaard OS, Graversen ME, Leth S, Olesen R, Brinkmann CR, Nissen SK, et al. The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo. PLoS Pathog. 2015;11(9):e1005142. doi: 10.1371/journal.ppat.1005142. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Deeks SG. HIV: Shock and kill. Nature. 2012;487(7408):439–440. doi: 10.1038/487439a. [DOI] [PubMed] [Google Scholar]
  • 27.Migueles SA, Sabbaghian MS, Shupert WL, Bettinotti MP, Marincola FM, Martino L, et al. HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors. Proc Natl Acad Sci U S A. 2000;97(6):2709–2714. doi: 10.1073/pnas.050567397. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Chen H, Ndhlovu ZM, Liu D, Porter LC, Fang JW, Darko S, et al. TCR clonotypes modulate the protective effect of HLA class I molecules in HIV-1 infection. Nature. 2012;13(7):691–700. doi: 10.1038/ni.2342. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Mudd PA, Martins MA, Ericsen AJ, Tully DC, Power KA, Bean AT, et al. Vaccine-induced CD8+ T cells control AIDS virus replication. Nature. 2012;491(7422):129–133. doi: 10.1038/nature11443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Pandrea I, Gaufin T, Gautam R, Kristoff J, Mandell D, Montefiori D, et al. Functional cure of SIVagm infection in rhesus macaques results in complete recovery of CD4+ T cells and is reverted by CD8+ cell depletion. PLoS Pathog. 2011;7(8):e1002170. doi: 10.1371/journal.ppat.1002170. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Fukazawa Y, Lum R, Okoye AA, Park H, Matsuda K, Bae JY, et al. B cell follicle sanctuary permits persistent productive simian immunodeficiency virus infection in elite controllers. Nat Med. 2015;21(2):132–139. doi: 10.1038/nm.3781. Reports that SIV-specific CD8 T cells contribute to control SIV replication in lymphoid tissues outside of the B cell follicles in elite controller macaques.
  • 32. Cartwright EK, Vanderford TH, Easley KA, Schmitz JE, Chahroudi A, Bosinger SE, et al. CD8 T Cells Are Required to Suppress Viremia in SIV-Infected ART Treated Macaques. CROI2016, Boston. 2016 Abstract 22. Reports that SIV-specific CD8 T cells contribute to control SIV replication in ART-treated macaques.
  • 33.Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. 2006;443(7109):350–354. doi: 10.1038/nature05115. [DOI] [PubMed] [Google Scholar]
  • 34.Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S, Bessette B, et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med. 2006;12(10):1198–1202. doi: 10.1038/nm1482. [DOI] [PubMed] [Google Scholar]
  • 35.Jones RB, Ndhlovu LC, Barbour JD, Sheth PM, Jha AR, Long BR, et al. Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection. J Exp Med. 2008;205(12):2763–2779. doi: 10.1084/jem.20081398. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A, et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol. 2009;10(1):29–37. doi: 10.1038/ni.1679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Gray CM, Lawrence J, Schapiro JM, Altman JD, Winters MA, Crompton M, et al. Frequency of class I HLA-restricted anti-HIV CD8+ T cells in individuals receiving highly active antiretroviral therapy (HAART) J Immunol. 1999;162(3):1780–1788. [PubMed] [Google Scholar]
  • 38.Kalams SA, Goulder PJ, Shea AK, Jones NG, Trocha AK, Ogg GS, et al. Levels of human immunodeficiency virus type 1-specific cytotoxic T-lymphocyte effector and memory responses decline after suppression of viremia with highly active antiretroviral therapy. J Virol. 1999;73(8):6721–6728. doi: 10.1128/jvi.73.8.6721-6728.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Ogg GS, Jin X, Bonhoeffer S, Moss P, Nowak MA, Monard S, et al. Decay kinetics of human immunodeficiency virus-specific effector cytotoxic T lymphocytes after combination antiretroviral therapy. J Virol. 1999;73(1):797–800. doi: 10.1128/jvi.73.1.797-800.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Casazza JP, Betts MR, Picker LJ, Koup RA. Decay kinetics of human immunodeficiency virus-specific CD8+ T cells in peripheral blood after initiation of highly active antiretroviral therapy. J Virol. 2001;75(14):6508–6516. doi: 10.1128/JVI.75.14.6508-6516.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Migueles SA, Weeks KA, Nou E, Berkley AM, Rood JE, Osborne CM, et al. Defective human immunodeficiency virus-specific CD8+ T-cell polyfunctionality, proliferation, and cytotoxicity are not restored by antiretroviral therapy. J Virol. 2009;83(22):11876–11889. doi: 10.1128/JVI.01153-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Janbazian L, Price DA, Canderan G, Filali-Mouhim A, Asher TE, Ambrozak DR, et al. Clonotype and Repertoire Changes Drive the Functional Improvement of HIV-Specific CD8 T Cell Populations under Conditions of Limited Antigenic Stimulation. J Immunol. 2012;188(3):1156–1167. doi: 10.4049/jimmunol.1102610. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Connick E, Mattila T, Folkvord JM, Schlichtemeier R, Meditz AL, Ray MG, et al. CTL fail to accumulate at sites of HIV-1 replication in lymphoid tissue. J Immunol. 2007;178(11):6975–6983. doi: 10.4049/jimmunol.178.11.6975. [DOI] [PubMed] [Google Scholar]
  • 44.Perreau M, Savoye AL, De Crignis E, Corpataux JM, Cubas R, Haddad EK, et al. Follicular helper T cells serve as the major CD4 T cell compartment for HIV-1 infection, replication, and production. J Exp Med. 2013;210(1):143–156. doi: 10.1084/jem.20121932. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45. Shan L, Deng K, Shroff NS, Durand CM, Rabi SA, Yang HC, et al. Stimulation of HIV-1-Specific Cytolytic T Lymphocytes Facilitates Elimination of Latent Viral Reservoir after Virus Reactivation. Immunity. 2012;36(3):491–501. doi: 10.1016/j.immuni.2012.01.014. Proof of concept for the expansion of HIV-specific CD8 T cells from ART-suppressed patients to eliminate reactivated latently-infected CD4 T cells.
  • 46.Hansen SG, Ford JC, Lewis MS, Ventura AB, Hughes CM, Coyne-Johnson L, et al. Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine. Nature. 2011;473(7348):523–527. doi: 10.1038/nature10003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47. Hansen SG, Piatak M, Jr, Ventura AB, Hughes CM, Gilbride RM, Ford JC, et al. Immune clearance of highly pathogenic SIV infection. Nature. 2013;502(7469):100–104. doi: 10.1038/nature12519. Reports SIV-specific CD8 T cells mediated clearance of SIV in macaques vaccinated with the ResusCMV vaccine inducing non-classical CD8 T cell responses and provides the proof of concept in vivo that HIV-specific CD8 T cells can purge the HIV reservoir.
  • 48.Hansen SG, Sacha JB, Hughes CM, Ford JC, Burwitz BJ, Scholz I, et al. Cytomegalovirus vectors violate CD8+ T cell epitope recognition paradigms. Science. 2013;340(6135):1237874. doi: 10.1126/science.1237874. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Hansen SG, Wu HL, Burwitz BJ, Hughes CM, Hammond KB, Ventura AB, et al. Broadly targeted CD8(+) T cell responses restricted by major histocompatibility complex E. Science. 2016;351(6274):714–720. doi: 10.1126/science.aac9475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Allan DS, Lepin EJ, Braud VM, O'Callaghan CA, McMichael AJ. Tetrameric complexes of HLA-E, HLA-F, and HLA-G. Journal of immunological methods. 2002;268(1):43–50. doi: 10.1016/s0022-1759(02)00199-0. [DOI] [PubMed] [Google Scholar]
  • 51.Pietra G, Romagnani C, Manzini C, Moretta L, Mingari MC. The emerging role of HLA-E-restricted CD8+ T lymphocytes in the adaptive immune response to pathogens and tumors. Journal of biomedicine & biotechnology. 2010;2010:907092. doi: 10.1155/2010/907092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.van Meijgaarden KE, Haks MC, Caccamo N, Dieli F, Ottenhoff TH, Joosten SA. Human CD8+ T-cells recognizing peptides from Mycobacterium tuberculosis (Mtb) presented by HLA-E have an unorthodox Th2-like, multifunctional, Mtb inhibitory phenotype and represent a novel human T-cell subset. PLoS Pathog. 2015;11(3):e1004671. doi: 10.1371/journal.ppat.1004671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Chun TW, Justement JS, Moir S, Hallahan CW, Ehler LA, Liu S, et al. Suppression of HIV replication in the resting CD4+ T cell reservoir by autologous CD8+ T cells: implications for the development of therapeutic strategies. Proc Natl Acad Sci USA. 2001;98(1):253–258. doi: 10.1073/pnas.98.1.253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Chun TW, Engel D, Berrey MM, Shea T, Corey L, Fauci AS. Early establishment of a pool of latently infected, resting CD4(+) T cells during primary HIV-1 infection. Proc Natl Acad Sci USA. 1998;95(15):8869–8873. doi: 10.1073/pnas.95.15.8869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Whitney JB, Hill AL, Sanisetty S, Penaloza-MacMaster P, Liu J, Shetty M, et al. Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys. Nature. 2014;512(7512):74–77. doi: 10.1038/nature13594. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Oxenius A, Price DA, Easterbrook PJ, O'Callaghan CA, Kelleher AD, Whelan JA, et al. Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of CD8+ and CD4+ T lymphocytes. Proc Natl Acad Sci U S A. 2000;97(7):3382–3387. doi: 10.1073/pnas.97.7.3382. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Altfeld M, Rosenberg ES, Shankarappa R, Mukherjee JS, Hecht FM, Eldridge RL, et al. Cellular immune responses and viral diversity in individuals treated during acute and early HIV-1 infection. J Exp Med. 2001;193(2):169–180. doi: 10.1084/jem.193.2.169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Hecht FM, Wang L, Collier A, Little S, Markowitz M, Margolick J, et al. A multicenter observational study of the potential benefits of initiating combination antiretroviral therapy during acute HIV infection. J Infect Dis. 2006;194(6):725–733. doi: 10.1086/506616. [DOI] [PubMed] [Google Scholar]
  • 59.Cellerai C, Harari A, Stauss H, Yerly S, Geretti A-M, Carroll A, et al. Early and Prolonged Antiretroviral Therapy Is Associated with an HIV-1-Specific T-Cell Profile Comparable to That of Long-Term Non-Progressors. PloS one. 2011;6(4):e18164. doi: 10.1371/journal.pone.0018164. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.von Wyl V, Gianella S, Fischer M, Niederoest B, Kuster H, Battegay M, et al. Early Antiretroviral Therapy During Primary HIV-1 Infection Results in a Transient Reduction of the Viral Setpoint upon Treatment Interruption. PloS one. 2011;6(11):e27463. doi: 10.1371/journal.pone.0027463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61. Ananworanich J, Schuetz A, Vandergeeten C, Sereti I, de Souza M, Rerknimitr R, et al. Impact of Multi-Targeted Antiretroviral Treatment on Gut T Cell Depletion and HIV Reservoir Seeding during Acute HIV Infection. PloS one. 2012;7(3):e33948. doi: 10.1371/journal.pone.0033948. Describes the impact of ART initiation in hyperacute infection on immune activation and HIV reservoir.
  • 62.Thornhill J, Inshaw J, Oomeer S, Kaleebu P, Cooper D, Ramjee G, et al. Enhanced normalisation of CD4/CD8 ratio with early antiretroviral therapy in primary HIV infection. Journal of the International AIDS Society. 2014;17(4 Suppl 3):19480. doi: 10.7448/IAS.17.4.19480. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Williams JP, Hurst J, Stohr W, Robinson N, Brown H, Fisher M, et al. HIV-1 DNA predicts disease progression and post-treatment virological control. Elife. 2014;3:e03821. doi: 10.7554/eLife.03821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Fidler S, Porter K, Ewings F, Frater J, Ramjee G, Cooper D, et al. Short-course antiretroviral therapy in primary HIV infection. N Engl J Med. 2013;368(3):207–217. doi: 10.1056/NEJMoa1110039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Stohr W, Fidler S, McClure M, Weber J, Cooper D, Ramjee G, et al. Duration of HIV-1 viral suppression on cessation of antiretroviral therapy in primary infection correlates with time on therapy. PloS one. 2013;8(10):e78287. doi: 10.1371/journal.pone.0078287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66. Hurst J, Hoffmann M, Pace M, Williams JP, Thornhill J, Hamlyn E, et al. Immunological biomarkers predict HIV-1 viral rebound after treatment interruption. Nature communications. 2015;6:8495. doi: 10.1038/ncomms9495. Reports that lower T cell immune activation prior to ART initiation is associated with delayed viral load rebound after ART interruption.
  • 67.Paci P, Martini F, Bernaschi M, D'Offizi G, Castiglione F. Timely HAART initiation may pave the way for a better viral control. BMC Infect Dis. 2011;11:56. doi: 10.1186/1471-2334-11-56. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MB. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J Virol. 1994;68(9):6103–6110. doi: 10.1128/jvi.68.9.6103-6110.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Koup RA, Safrit JT, Cao Y, Andrews CA, McLeod G, Borkowsky W, et al. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol. 1994;68(7):4650–4655. doi: 10.1128/jvi.68.7.4650-4655.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Freel SA, Picking RA, Ferrari G, Ding H, Ochsenbauer C, Kappes JC, et al. Initial HIV-1 Antigen-Specific CD8+ T Cells in Acute HIV-1 Infection Inhibit Transmitted/Founder Virus Replication. J Virol. 2012;86(12):6835–6846. doi: 10.1128/JVI.00437-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71.Ndhlovu ZM, Kamya P, Mewalal N, Kloverpris HN, Nkosi T, Pretorius K, et al. Magnitude and Kinetics of CD8+ T Cell Activation during Hyperacute HIV Infection Impact Viral Set Point. Immunity. 2015;43(3):591–604. doi: 10.1016/j.immuni.2015.08.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72.Trautmann L, Mbitikon-Kobo FM, Goulet J-P, Peretz Y, Shi Y, Van Grevenynghe J, et al. Profound metabolic, functional, and cytolytic differences characterize HIV-specific CD8 T cells in primary and chronic HIV infection. Blood. 2012;120(17):3466–3477. doi: 10.1182/blood-2012-04-422550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Minang JT, Barsov EV, Yuan F, Trivett MT, Piatak M, Jr, Lifson JD, et al. Efficient inhibition of SIV replication in rhesus CD4+ T-cell clones by autologous immortalized SIV-specific CD8+ T-cell clones. Virology. 2008;372(2):430–441. doi: 10.1016/j.virol.2007.11.013. [DOI] [PubMed] [Google Scholar]
  • 74.Bolton DL, Minang JT, Trivett MT, Song K, Tuscher JJ, Li Y, et al. Trafficking, persistence, and activation state of adoptively transferred allogeneic and autologous Simian Immunodeficiency Virus-specific CD8(+) T cell clones during acute and chronic infection of rhesus macaques. J Immunol. 2010;184(1):303–314. doi: 10.4049/jimmunol.0902413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Minang JT, Trivett MT, Bolton DL, Trubey CM, Estes JD, Li Y, et al. Distribution, persistence, and efficacy of adoptively transferred central and effector memory-derived autologous simian immunodeficiency virus-specific CD8+ T cell clones in rhesus macaques during acute infection. J Immunol. 2010;184(1):315–326. doi: 10.4049/jimmunol.0902410. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76.Sung JA, Lam S, Garrido C, Archin N, Rooney CM, Bollard CM, et al. Expanded cytotoxic T-cell lymphocytes target the latent HIV reservoir. J Infect Dis. 2015;212(2):258–263. doi: 10.1093/infdis/jiv022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Restifo NP, Dudley ME, Rosenberg SA. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat Rev Immunol. 2012;12(4):269–281. doi: 10.1038/nri3191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78. Chapuis AG, Casper C, Kuntz S, Zhu J, Tjernlund A, Diem K, et al. HIV-specific CD8+ T cells from HIV+ individuals receiving HAART can be expanded ex vivo to augment systemic and mucosal immunity in vivo. Blood. 2011;117(20):5391–5402. doi: 10.1182/blood-2010-11-320226. Describes long term persistence of HIV-specific CD8 T cells in vivo after adoptive cell transfer of in ART-treated individuals.
  • 79.Carcelain G, Autran B. Immune interventions in HIV infection. Immunol Rev. 2013;254(1):355–371. doi: 10.1111/imr.12083. [DOI] [PubMed] [Google Scholar]
  • 80.Graziani GM, Angel JB. Evaluating the efficacy of therapeutic HIV vaccines through analytical treatment interruptions. Journal of the International AIDS Society. 2015;18:20497. doi: 10.7448/IAS.18.1.20497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.Mylvaganam GH, Silvestri G, Amara RR. HIV therapeutic vaccines: moving towards a functional cure. Curr Opin Immunol. 2015;35:1–8. doi: 10.1016/j.coi.2015.05.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82. Deng K, Pertea M, Rongvaux A, Wang L, Durand CM, Ghiaur G, et al. Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations. Nature. 2015;517(7534):381–385. doi: 10.1038/nature14053. Describe the ability of broad CD8 T cell responses to clear HIV reservoir and provides the proof of concept that broad CD8 T cells need to be induced by immunobased strategies.
  • 83.Wang FX, Xu Y, Sullivan J, Souder E, Argyris EG, Acheampong EA, et al. IL-7 is a potent and proviral strain-specific inducer of latent HIV-1 cellular reservoirs of infected individuals on virally suppressive HAART. J Clin Invest. 2005;115(1):128–137. doi: 10.1172/JCI22574. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.Darcis G, Kula A, Bouchat S, Fujinaga K, Corazza F, Ait-Ammar A, et al. An In-Depth Comparison of Latency-Reversing Agent Combinations in Various In Vitro and Ex Vivo HIV-1 Latency Models Identified Bryostatin-1+JQ1 and Ingenol-B+JQ1 to Potently Reactivate Viral Gene Expression. PLoS Pathog. 2015;11(7):e1005063. doi: 10.1371/journal.ppat.1005063. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85.Offersen R, Nissen SK, Rasmussen T, Ostergaard L, Denton PW, Sogaard OS, et al. A novel toll-like receptor-9 agonist, MGN1703, enhances HIV-1 transcription and NK cell-mediated inhibition of HIV-1 infected autologous CD4+ T cells. J Virol. 2016 doi: 10.1128/JVI.00222-16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86.Whitney JB, Lim SY, Osuna CE, Sanisetty SS, Barnes TL, Cihlar T, et al. Repeated TLR7 Agonist Treatment of SIV+ Monkeys on ART Can Lead to Viral Remission. CROI2016, Boston. 2016 Abstract 95LB. [Google Scholar]
  • 87.Eron JJ, Gay C, Bosch R, Ritz J, Hataye JM, Hwang C, et al. Safety, Immunologic and Virologic Activity of Anti-PD-L1 in HIV-1 Participants on ART. CROI2016, Boston. 2016 Abstract 25. [Google Scholar]
  • 88.Li Q, Skinner PJ, Ha SJ, Duan L, Mattila TL, Hage A, et al. Visualizing antigen-specific and infected cells in situ predicts outcomes in early viral infection. Science. 2009;323(5922):1726–1729. doi: 10.1126/science.1168676. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89.Appay V, Douek DC, Price DA. CD8+ T cell efficacy in vaccination and disease. Nat Med. 2008;14(6):623–628. doi: 10.1038/nm.f.1774. [DOI] [PubMed] [Google Scholar]
  • 90.Betts MR, Harari A. Phenotype and function of protective T cell immune responses in HIV. Curr Opin HIV AIDS. 2008;3(3):349–355. doi: 10.1097/COH.0b013e3282fbaa81. [DOI] [PubMed] [Google Scholar]
  • 91.Mbitikon-Kobo FM, Bonneville M, Sekaly RP, Trautmann L. Ex vivo measurement of the cytotoxic capacity of human primary antigen-specific CD8 T cells. Journal of immunological methods. 2012;375(1–2):252–257. doi: 10.1016/j.jim.2011.09.008. [DOI] [PubMed] [Google Scholar]
  • 92.Noto A, Ngauv P, Trautmann L. Cell-based flow cytometry assay to measure cytotoxic activity. Journal of visualized experiments : JoVE. 2013(82):e51105. doi: 10.3791/51105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 93. Sáez-Cirión A, Shin SY, Versmisse P, Barré-Sinoussi F, Pancino G. Ex vivo T cell–based HIV suppression assay to evaluate HIV-specific CD8+ T-cell responses. Nature Protocols. 2010;5(6):1033–1041. doi: 10.1038/nprot.2010.73. Describes an assay to measure the inhibition of HIV replication by CD8 T cells.
  • 94.Spentzou A, Bergin P, Gill D, Cheeseman H, Ashraf A, Kaltsidis H, et al. Viral Inhibition Assay: A CD8 T Cell Neutralization Assay for Use in Clinical Trials of HIV-1 Vaccine Candidates. J Infect Dis. 2010;201(5):720–729. doi: 10.1086/650492. [DOI] [PubMed] [Google Scholar]
  • 95.Slichter CK, Friedrich DP, Smith RJ, Walsh PN, Mize G, Czartoski JL, et al. Measuring inhibition of HIV replication by ex vivo CD8(+) T cells. Journal of immunological methods. 2014;404:71–80. doi: 10.1016/j.jim.2013.12.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 96.Yang H, Wu H, Hancock G, Clutton G, Sande N, Xu X, et al. Antiviral Inhibitory Capacity of CD8+ T cells Predicts the Rate of CD4+ T-Cell Decline in HIV-1 Infection. J Infect Dis. 2012;206(4):552–561. doi: 10.1093/infdis/jis379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 97.Jones RB, O'Connor R, Mueller S, Foley M, Szeto GL, Karel D, et al. Histone deacetylase inhibitors impair the elimination of HIV-infected cells by cytotoxic T-lymphocytes. PLoS Pathog. 2014;10(8):e1004287. doi: 10.1371/journal.ppat.1004287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 98.Hill AL, Rosenbloom DI, Fu F, Nowak MA, Siliciano RF. Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1. Proc Natl Acad Sci U S A. 2014;111(37):13475–13480. doi: 10.1073/pnas.1406663111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 99.Razooky BS, Pai A, Aull K, Rouzine IM, Weinberger LS. A hardwired HIV latency program. Cell. 2015;160(5):990–1001. doi: 10.1016/j.cell.2015.02.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 100.Rouzine IM, Weinberger AD, Weinberger LS. An evolutionary role for HIV latency in enhancing viral transmission. Cell. 2015;160(5):1002–1012. doi: 10.1016/j.cell.2015.02.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 101.Perelson AS, Ribeiro RM. Modeling the within-host dynamics of HIV infection. BMC Biol. 2013;11:96. doi: 10.1186/1741-7007-11-96. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 102. Conway JM, Perelson AS. Post-treatment control of HIV infection. Proc Natl Acad Sci U S A. 2015;112(17):5467–5472. doi: 10.1073/pnas.1419162112. rovides mathematical prediction on immune responses strength and HIV reservoir size to achieve post treatment control after ART interruption.
  • 103.Smith NM, Mlcochova P, Watters SA, Aasa-Chapman MM, Rabin N, Moore S, et al. Proof-of-Principle for Immune Control of Global HIV-1 Reactivation In Vivo. Clin Infect Dis. 2015;61(1):120–128. doi: 10.1093/cid/civ219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 104.Pinkevych M, Cromer D, Tolstrup M, Grimm AJ, Cooper DA, Lewin SR, et al. HIV Reactivation from Latency after Treatment Interruption Occurs on Average Every 5–8 Days--Implications for HIV Remission. PLoS Pathog. 2015;11(7):e1005000. doi: 10.1371/journal.ppat.1005000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 105.Yates A, Graw F, Barber DL, Ahmed R, Regoes RR, Antia R. Revisiting estimates of CTL killing rates in vivo. PloS one. 2007;2(12):e1301. doi: 10.1371/journal.pone.0001301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 106.Petravic J, Martyushev A, Reece JC, Kent SJ, Davenport MP. Modeling the timing of antilatency drug administration during HIV treatment. J Virol. 2014;88(24):14050–14056. doi: 10.1128/JVI.01701-14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 107.Chomont N, El-Far M, Ancuta P, Trautmann L, Procopio FA, Yassine-Diab B, et al. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med. 2009;15(8):893–900. doi: 10.1038/nm.1972. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 108.Cary DC, Fujinaga K, Peterlin BM. Molecular mechanisms of HIV latency. J Clin Invest. 2016;126(2):448–454. doi: 10.1172/JCI80565. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 109.Pace MJ, Graf EH, Agosto LM, Mexas AM, Male F, Brady T, et al. Directly infected resting CD4+T cells can produce HIV Gag without spreading infection in a model of HIV latency. PLoS Pathog. 2012;8(7):e1002818. doi: 10.1371/journal.ppat.1002818. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 110.Buckheit RW, 3rd, Siliciano RF, Blankson JN. Primary CD8+ T cells from elite suppressors effectively eliminate non-productively HIV-1 infected resting and activated CD4+ T cells. Retrovirology. 2013;10:68. doi: 10.1186/1742-4690-10-68. [DOI] [PMC free article] [PubMed] [Google Scholar]

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