Advertisement
Mayo Clinic Proceedings Home

Can HIV Be Cured and Should We Try?

      An estimated 35 million people live with human immunodeficiency virus (HIV); 2.1 million new infections occurred and 1.5 million persons died of HIV in 2013.

      World Health Organization. Global summary of the AIDS epidemic 2013. http://www.who.int/hiv/data/epi_core_dec2014.png?ua=1. March 30, 2015.

      Despite effective combination antiretroviral therapy (cART), less than one-quarter of patients can access these life-prolonging medications. Despite its effectiveness, cART does not normalize life expectancy because premature aging, metabolic complications, and chronic inflammation complicate HIV therapy.
      HIV is incurable because of the presence of a latent viral reservoir. During the life cycle of the virus, HIV integrates into the host DNA. A subset of integrated HIV provirus remains transcriptionally silent, producing neither viral proteins nor viral progeny, until reactivation by various physiologic stimuli. This latency of HIV allows some infected cells to escape immune detection and elimination, and these latently infected cells constitute the viral reservoir. The latent viral reservoir allows viral rebound within weeks of interruption of cART,
      • Jubault V.
      • Burgard M.
      • Le Corfec E.
      • Costagliola D.
      • Rouzioux C.
      • Viard J.P.
      High rebound of plasma and cellular HIV load after discontinuation of triple combination therapy.
      • Ruiz L.
      • Martinez-Picado J.
      • Romeu J.
      • et al.
      Structured treatment interruption in chronically HIV-1 infected patients after long-term viral suppression.
      where the magnitude of viral replication approaches that present pretherapy. Although it was once thought that viral rebound occurred universally after therapy interruption, several recent reports challenge that paradigm. In the Berlin patient, HIV was successfully cleared after 2 allogeneic transplants from a donor with homozygous CCR5Δ32 mutation,
      • Hutter G.
      • Nowak D.
      • Mossner M.
      • et al.
      Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation.
      and HIV has not recurred in this patient after nearly 7 years. This case likely represents a cure of HIV; however, other cases have been described in which HIV recurrence has been attenuated or delayed. The Mississippi infant was a perinatally HIV-infected infant who initiated cART within hours of birth, and when treatment was interrupted 8 months later, viremia remained undetectable for nearly 2 years.
      • Persaud D.
      • Gay H.
      • Ziemniak C.
      • et al.
      Absence of detectable HIV-1 viremia after treatment cessation in an infant.
      The Harvard patients who underwent allogeneic bone marrow transplantation developed undetectable HIV DNA, yet viremia recurred within only 8 months after cART discontinuation.
      • Henrich T.J.
      • Hanhauser E.
      • Marty F.M.
      • et al.
      Antiretroviral-free HIV-1 remission and viral rebound after allogeneic stem cell transplantation: report of 2 cases.
      Together these cases indicate that control of viremia in the absence of cART is possible, if not durable.
      • Persaud D.
      • Gay H.
      • Ziemniak C.
      • et al.
      Absence of detectable HIV-1 viremia after treatment cessation in an infant.
      The Virological and Immunological Studies in Controllers after Treatment Interruption (VISCONTI) cohort of 14 HIV-infected adults who initiated antiretroviral therapy during acute infection and in whom high-level rebound viremia had not occurred several years after cessation of therapy
      • Saez-Cirion A.
      • Bacchus C.
      • Hocqueloux L.
      • et al.
      Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study.
      similarly found that viral rebound after cART interruption can be attenuated.
      These cases have reinvigorated research toward finding a cure for HIV, which certainly will require an exceptional investment of time, talent, and resources. Thus, it is prudent to question whether such resources would be better devoted to more proximate needs with proven results (such as supplying cART to those without access to it or supplying pre- or postexposure prophylaxis to reduce the rate of new infections).

      Limitations

      To target something for eradication (without inducing unacceptable collateral damage) one must first be able to define and identify it. Many details of the latent HIV reservoir remain unknown, including what cell types make up the latent reservoir, the actual size of the reservoir, and its anatomical location(s). Although central memory CD4 T cells contribute to the reservoir, HIV infects a number of other cell types with long half-lives, including tissue macrophages and microglia, which reside in immunologically and pharmacologically protected anatomical sites (eg, testes and central nervous system).
      • Haggerty C.M.
      • Pitt E.
      • Siliciano R.F.
      The latent reservoir for HIV-1 in resting CD4+ T cells and other viral reservoirs during chronic infection: insights from treatment and treatment-interruption trials.
      Furthermore, HIV can infect CD34+ hematopoietic stem cells,
      • Carter C.C.
      • Onafuwa-Nuga A.
      • McNamara L.A.
      • et al.
      HIV-1 infects multipotent progenitor cells causing cell death and establishing latent cellular reservoirs.
      • McNamara L.A.
      • Ganesh J.A.
      • Collins K.L.
      Latent HIV-1 infection occurs in multiple subsets of hematopoietic progenitor cells and is reversed by NF-kappaB activation.
      suggesting that potentially any cell derived from hematopoietic stem cells could contain latent virus.
      It also remains unknown what HIV characteristics are necessary to be considered a true reservoir because integrated proviral DNA can be replication competent or incompetent because of fatal mutations in the viral complementary DNA before integration and/or the presence of deletions within the viral genome. Thus, transcription has to be induced to reactivate viral replication and provide pharmacologic or immunologic targets, the so-called shock-and-kill hypothesis, which has 3 main limitations. First, although there are several models of HIV latency, none fully recapitulate what occurs in vivo, and experimental results in one model rarely are replicable in another.
      • Spina C.A.
      • Anderson J.
      • Archin N.M.
      • et al.
      An in-depth comparison of latent HIV-1 reactivation in multiple cell model systems and resting CD4+ T cells from aviremic patients.
      Second, no potentially clinically acceptable reactivation stimulus has been described that reactivates provirus in all in vitro models or even all provirus in a single model.
      • Bullen C.K.
      • Laird G.M.
      • Durand C.M.
      • Siliciano J.D.
      • Siliciano R.F.
      New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo.
      Third, up to 12% of noninduced proviruses are replication competent, as determined by cloning and in vitro infection assays,
      • Ho Y.C.
      • Shan L.
      • Hosmane N.N.
      • et al.
      Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure.
      suggesting that viral reactivation with available agents is incomplete.
      All cure strategies envision concurrent suppressive cART in addition to the cure intervention. However, nearly 1 in 5 HIV-infected people do not know they are infected,
      Vital signs: HIV prevention through care and treatment–United States.
      and they continue to transmit HIV. Furthermore, fewer than 1 in 3 who know they are HIV infected successfully suppress viral replication with therapy.
      Vital signs: HIV prevention through care and treatment–United States.
      Therefore, a cure would be available to less than 25% of persons in resource-rich countries, and fewer worldwide, unless significant improvements are made in HIV diagnosis, access to care, and effective treatment.
      Although viral eradication would be ideal, achieving a functional cure is considered more realistic, wherein altering host susceptibility to infection, or through boosting immune control of viral replication, a new homeostasis is achieved between virus and host, and progression to AIDS is prevented without the need for antiretroviral therapy. A small percentage of HIV-infected persons already control disease as natural variants to the expected clinical course of the disease. Long-term nonprogressors are characterized by having preserved CD4 T-cell counts for a long period (typically >10 years), despite ongoing moderate- to high-level viral replication. Elite controllers also maintain preserved CD4 T-cell counts but in the setting of immune-based control of viral replication to low levels. However, LNTPs eventually progress and some elite controllers eventually lose virologic control, both situations requiring initiation of antiretroviral therapy.
      • Rodes B.
      • Toro C.
      • Paxinos E.
      • et al.
      Differences in disease progression in a cohort of long-term non-progressors after more than 16 years of HIV-1 infection.
      Furthermore, long-term nonprogressors and elite controllers still have complications of chronic inflammation, suggesting that patients with functional cure may not escape all the consequences of persistent HIV infection.

      Crowell TA, Gebo KA, Blankson JN, et al. Hospitalization rates and reasons among HIV elite controllers and persons with medically controlled HIV infection [published online December 15, 2014]. J Infect Dis. http://dx.doi.org/10.1093/infdis/jiu809.

      Therefore, if the goal of HIV cure is to avoid lifelong cART and chronic inflammation, the clinical experience of long-term nonprogressors and elite controllers suggests that viral eradication should ultimately be the target, which is arguably more difficult to attain than a functional cure.

      Hope for the Future

      Nevertheless, the fact that the Berlin patient has been cured means ipso facto that HIV can be cured. As research seeks to recapitulate that cure in a more generalizable way, it is prudent to keep in mind the desirable attributes of a cure. The cure must be less toxic than lifelong cART, the cure must be generalizable and available not only in a handful of specialized institutions, and the cure must be scalable to reach most infected patients worldwide. Failure to achieve these criteria will necessarily limit the access to and uptake of the cure in a global setting. Although stem cell transplantation with donor cells genetically resistant to infection has resulted in the only HIV cure to date, and infusion of autologous CD4 T cells genetically engineered to become resistant to infection have been found to persist in HIV-infected patients,
      • Tebas P.
      • Stein D.
      • Tang W.W.
      • et al.
      Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV.
      we believe that stem cell transplant-related strategies and complex gene therapies are effectively impractical as large-scale interventions but maintain value as a means of testing proof of concept. Three broad approaches are discussed below that we believe offer better hope for a generalizable HIV cure in the attainable future.

       Prime, Shock, and Kill

      An early theoretical approach to HIV eradication was based on the premise that because many HIV-encoded proteins are intrinsically cytotoxic, reactivating HIV from a formerly latent CD4 T cell would result in the intracellular expression of these cytotoxic proteins and result in cell death by apoptosis (often incorrectly referred to as lysis or cytolysis).
      • Deeks S.G.
      HIV: Shock and kill.
      However, when this shock-and-kill hypothesis was tested, cell death did not occur.
      • Shan L.
      • Deng K.
      • Shroff N.S.
      • et al.
      Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation.
      • Bosque A.
      • Famiglietti M.
      • Weyrich A.S.
      • Goulston C.
      • Planelles V.
      Homeostatic proliferation fails to efficiently reactivate HIV-1 latently infected central memory CD4+ T cells.
      Because latent HIV resides principally in central memory CD4 T cells, which function as a long-lived archive of immune responses, the resistance of these cells to death after HIV reactivation may simply be due to these cells being destined to longevity and thus resistant to death. Thus, we (A.D.B) have proposed a modification wherein chemosensitization (instructed by years of oncology chemosensitization strategies) of central memory cells toward an apoptosis-prone phenotype before HIV reactivation will achieve a decrease in latently infected cell number.
      • Badley A.D.
      • Sainski A.
      • Wightman F.
      • Lewin S.R.
      Altering cell death pathways as an approach to cure HIV infection.

       Broadly Neutralizing Antibodies (With Cellular Cytotoxicity Mechanisms)

      Prophylactic and therapeutic vaccines are promising in nonhuman primate models of HIV infection.
      • Barouch D.H.
      • Stephenson K.E.
      • Borducchi E.N.
      • et al.
      Protective efficacy of a global HIV-1 mosaic vaccine against heterologous SHIV challenges in rhesus monkeys.
      • Hansen S.G.
      • Piatak Jr., M.
      • Ventura A.B.
      • et al.
      Immune clearance of highly pathogenic SIV infection.
      However, human trials of vaccine-based approaches to control of HIV have been widely disappointing, with the exception of one trial, which found a modest reduction in HIV acquisition rates.
      • Rerks-Ngarm S.
      • Pitisuttithum P.
      • Nitayaphan S.
      • et al.
      Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand.
      Reasons why so many vaccine trials have failed and the Thai trial succeeded (despite using the same immunogens that failed in previous trials) are unknown but may be illuminated by studies in macaques, which reveal that vaccine response and protection from infectious challenge is affected by genetic background.
      • Mudd P.A.
      • Martins M.A.
      • Ericsen A.J.
      • et al.
      Vaccine-induced CD8+ T cells control AIDS virus replication.
      Thus, the successful Thai trial might have succeeded where the same vaccine had failed previously because it was tested in a new genetic background. Vaccine studies might therefore best be tested in a design that controls for HLA background; doing so might allow discrimination of a beneficial effect in select subgroups.
      Another promising approach involves the concept of broadly neutralizing antibodies. Although not a novel concept in infectious disease therapy, only recently have several broadly neutralizing antibodies been identified that neutralize more than 90% of clinical HIV isolates.
      • Klein F.
      • Halper-Stromberg A.
      • Horwitz J.A.
      • et al.
      HIV therapy by a combination of broadly neutralizing antibodies in humanized mice.
      Moreover, there has been recent recognition that modifications to the Fc domain of antibodies greatly affect the engagement of cells that bind antibodies and affect the cellular mechanisms of immune clearance after antibody binding (egg, antibody-dependent cellular cytotoxicity and phagocytosis). Thus, creation of a synthetic antibody whose Fab domains neutralize more than 90% of HIV isolates merged with an optimized Fc domain that optimally activates antibody-dependent cellular cytotoxicity and other cellular clearance pathways offers promise as a long-lasting antiviral agent.
      • Bournazos S.
      • Klein F.
      • Pietzsch J.
      • Seaman M.S.
      • Nussenzweig M.C.
      • Ravetch J.V.
      Broadly neutralizing anti-HIV-1 antibodies require Fc effector functions for in vivo activity.
      • Halper-Stromberg A.
      • Lu C.L.
      • Klein F.
      • et al.
      Broadly neutralizing antibodies and viral inducers decrease rebound from HIV-1 latent reservoirs in humanized mice.
      How it might be used remains to be determined, but whereas pharmacologic antiviral intensification fails to suppress HIV replication to less than 1 copy/mL, neutralizing antibody therapy might, thereby preventing low-level viremia repopulating the HIV reservoir.

      Immune-Boosting Strategies

      It is now widely accepted that persons infected with HIV mount a broad immune response to the virus but that the immune response fails to control viral replication or kill most virally infected cells. Reasons why the immune response is ineffective are likely multiple but clearly include inappropriate expression of immune inhibitory receptors, such as PD-1, CTLA-4, and others. With this background, inhibitors of the ligand for PD-1, which have recently been approved by the Food and Drug Administration for immune boosting during therapy of refractory melanoma, are likely to augment the quality of the anti-HIV T-cell response, possibly achieving meaningful reductions in HIV burden.
      • Seung E.
      • Dudek T.E.
      • Allen T.M.
      • Freeman G.J.
      • Luster A.D.
      • Tager A.M.
      PD-1 blockade in chronically HIV-1-infected humanized mice suppresses viral loads.
      Similarly, studies of CTLA-4 inhibitors will be of great interest as complementary immune-boosting strategies. It is notable, though, that other immune-based strategies, including administration of the stimulatory cytokines interleukin 2 and interleukin 7, actually increased the size of the latent HIV reservoir.
      • Delaugerre C.
      • Gourlain K.
      • Tubiana R.
      • et al.
      Increase of HIV-1 pro-viral DNA per million peripheral blood mononuclear cells in patients with advanced HIV disease (CD4<200 cells/mm3) receiving interleukin 2 combined with HAART versus HAART alone (ANRS-082 trial).
      • Vandergeeten C.
      • Fromentin R.
      • DaFonseca S.
      • et al.
      Interleukin-7 promotes HIV persistence during antiretroviral therapy.

      How Low is Low Enough?

      A critical challenge facing the cure initiative is to understand when interventions have reduced the HIV burden low enough that HIV will not come back after antiretroviral therapy is stopped. In fact, recent mathematical modeling suggests that the latent viral reservoir would need to be reduced more than 10,000-fold to achieve an eradication cure.
      • Hill A.L.
      • Rosenbloom D.I.
      • Fu F.
      • Nowak M.A.
      • Siliciano R.F.
      Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1.
      Even in the case of the only patient cured of HIV to date, both HIV RNA and DNA were detectable at various times.
      • Yukl S.A.
      • Boritz E.
      • Busch M.
      • et al.
      Challenges in detecting HIV persistence during potentially curative interventions: a study of the Berlin patient.
      Thus, absence of HIV nucleic acid is not necessary for cure. This is perhaps understandable, given that approximately 80% of integrated proviruses are defective (ie, uninducible).
      What then is the measure that we should use to predict when a cure has been achieved? One possible laboratory surrogate for HIV cure is the quantitative viral outgrowth assay (QVOA), which measures how much replication-competent HIV is present in peripheral blood. The predictive ability of QVOA will, of course, depend on how many input cells are tested. Ultimately, the benchmark test of cure will be absence of HIV rebound after antiretroviral stoppage.

      How Best to Achieve a Cure?

      It is likely that several, or even many, strategies will be identified that can reduce HIV burden to some degree. By acting on different pathways to reduce HIV burden or by applying sequential interventions, these different treatment modalities may be additive or possibly synergistic in their anti-HIV effects. For instance, there are substantial data that treatment with cART during acute HIV infection significantly restricts the size of the latent viral reservoir.
      • Buzon M.J.
      • Martin-Gayo E.
      • Pereyra F.
      • et al.
      Long-term antiretroviral treatment initiated at primary HIV-1 infection affects the size, composition, and decay kinetics of the reservoir of HIV-1-infected CD4 T cells.
      • Ananworanich J.
      • Dube K.
      • Chomont N.
      How does the timing of antiretroviral therapy initiation in acute infection affect HIV reservoirs?.
      These patients may ultimately then benefit from subsequent curative interventions with otherwise modest effects on the reservoir. Much as antiretroviral effects were only optimized by the additive effects of different drug classes, the likely path to HIV cure will involve multiple different HIV reservoir–reducing agents, given with maximally suppressive cART, until such time that a predictive assay, such as the QVOA, suggests that cure might have occurred, at which point the patient and physician decide whether antiretroviral therapy should be stopped and the patient monitored closely for viral rebound.

      Conclusion

      We believe, and we think most in the scientific community would agree, that finding a cure for HIV is indeed a laudable goal and that expanding research effort in that direction is warranted. It remains debatable whether an actual cure is within reach. However, basic science, clinical, and epidemiologic research in HIV during the past 33 years has afforded a significant number of insights and methods that have translated across fields and advanced many other areas of science, such as development of lentiviral vector–mediated gene delivery, plerixafor for mobilization of hematopoietic stem cells before stem cell transplantation, treatment protocols for opportunistic infections in non-AIDS immunocompromised patients, and adaptive clinical trial design. It is likely that this ancillary benefit will continue to occur moving forward. However, we caution against irrational exuberance and suggest that the limited resources devoted to other proven prevention strategies (eg, prevention of mother-to-child transmission, preexposure prophylaxis, early postexposure treatment, male circumcision, and screening and education programs), the search for an effective vaccine, and expanding access to antiretroviral therapy should not be diverted from these worthy causes.

      Supplemental Online Material

      References

      1. World Health Organization. Global summary of the AIDS epidemic 2013. http://www.who.int/hiv/data/epi_core_dec2014.png?ua=1. March 30, 2015.

        • Jubault V.
        • Burgard M.
        • Le Corfec E.
        • Costagliola D.
        • Rouzioux C.
        • Viard J.P.
        High rebound of plasma and cellular HIV load after discontinuation of triple combination therapy.
        AIDS. 1998; 12: 2358-2359
        • Ruiz L.
        • Martinez-Picado J.
        • Romeu J.
        • et al.
        Structured treatment interruption in chronically HIV-1 infected patients after long-term viral suppression.
        AIDS. 2000; 14: 397-403
        • Hutter G.
        • Nowak D.
        • Mossner M.
        • et al.
        Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation.
        N Engl J Med. 2009; 360: 692-698
        • Persaud D.
        • Gay H.
        • Ziemniak C.
        • et al.
        Absence of detectable HIV-1 viremia after treatment cessation in an infant.
        N Engl J Med. 2013; 369: 1828-1835
        • Henrich T.J.
        • Hanhauser E.
        • Marty F.M.
        • et al.
        Antiretroviral-free HIV-1 remission and viral rebound after allogeneic stem cell transplantation: report of 2 cases.
        Ann Intern Med. 2014; 161: 319-327
        • Saez-Cirion A.
        • Bacchus C.
        • Hocqueloux L.
        • 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: e1003211
        • Haggerty C.M.
        • Pitt E.
        • Siliciano R.F.
        The latent reservoir for HIV-1 in resting CD4+ T cells and other viral reservoirs during chronic infection: insights from treatment and treatment-interruption trials.
        Curr Opin HIV AIDS. 2006; 1: 62-68
        • Carter C.C.
        • Onafuwa-Nuga A.
        • McNamara L.A.
        • et al.
        HIV-1 infects multipotent progenitor cells causing cell death and establishing latent cellular reservoirs.
        Nat Med. 2010; 16: 446-451
        • McNamara L.A.
        • Ganesh J.A.
        • Collins K.L.
        Latent HIV-1 infection occurs in multiple subsets of hematopoietic progenitor cells and is reversed by NF-kappaB activation.
        J Virol. 2012; 86: 9337-9350
        • Spina C.A.
        • Anderson J.
        • Archin N.M.
        • et al.
        An in-depth comparison of latent HIV-1 reactivation in multiple cell model systems and resting CD4+ T cells from aviremic patients.
        PLoS Pathog. 2013; 9: e1003834
        • Bullen C.K.
        • Laird G.M.
        • Durand C.M.
        • Siliciano J.D.
        • Siliciano R.F.
        New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo.
        Nat Med. 2014; 20: 425-429
        • Ho Y.C.
        • Shan L.
        • Hosmane N.N.
        • et al.
        Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure.
        Cell. 2013; 155: 540-551
      2. Vital signs: HIV prevention through care and treatment–United States.
        MMWR Morb Mortal Wkly Rep. 2011; 60: 1618-1623
        • Rodes B.
        • Toro C.
        • Paxinos E.
        • et al.
        Differences in disease progression in a cohort of long-term non-progressors after more than 16 years of HIV-1 infection.
        AIDS. 2004; 18: 1109-1116
      3. Crowell TA, Gebo KA, Blankson JN, et al. Hospitalization rates and reasons among HIV elite controllers and persons with medically controlled HIV infection [published online December 15, 2014]. J Infect Dis. http://dx.doi.org/10.1093/infdis/jiu809.

        • Tebas P.
        • Stein D.
        • Tang W.W.
        • et al.
        Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV.
        N Engl J Med. 2014; 370: 901-910
        • Deeks S.G.
        HIV: Shock and kill.
        Nature. 2012; 487: 439-440
        • Shan L.
        • Deng K.
        • Shroff N.S.
        • et al.
        Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation.
        Immunity. 2012; 36: 491-501
        • Bosque A.
        • Famiglietti M.
        • Weyrich A.S.
        • Goulston C.
        • Planelles V.
        Homeostatic proliferation fails to efficiently reactivate HIV-1 latently infected central memory CD4+ T cells.
        PLoS Pathog. 2011; 7: e1002288
        • Badley A.D.
        • Sainski A.
        • Wightman F.
        • Lewin S.R.
        Altering cell death pathways as an approach to cure HIV infection.
        Cell Death Dis. 2013; 4: e718
        • Barouch D.H.
        • Stephenson K.E.
        • Borducchi E.N.
        • et al.
        Protective efficacy of a global HIV-1 mosaic vaccine against heterologous SHIV challenges in rhesus monkeys.
        Cell. 2013; 155: 531-539
        • Hansen S.G.
        • Piatak Jr., M.
        • Ventura A.B.
        • et al.
        Immune clearance of highly pathogenic SIV infection.
        Nature. 2013; 502: 100-104
        • Rerks-Ngarm S.
        • Pitisuttithum P.
        • Nitayaphan S.
        • et al.
        Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand.
        N Engl J Med. 2009; 361: 2209-2220
        • Mudd P.A.
        • Martins M.A.
        • Ericsen A.J.
        • et al.
        Vaccine-induced CD8+ T cells control AIDS virus replication.
        Nature. 2012; 491: 129-133
        • Klein F.
        • Halper-Stromberg A.
        • Horwitz J.A.
        • et al.
        HIV therapy by a combination of broadly neutralizing antibodies in humanized mice.
        Nature. 2012; 492: 118-122
        • Bournazos S.
        • Klein F.
        • Pietzsch J.
        • Seaman M.S.
        • Nussenzweig M.C.
        • Ravetch J.V.
        Broadly neutralizing anti-HIV-1 antibodies require Fc effector functions for in vivo activity.
        Cell. 2014; 158: 1243-1253
        • Halper-Stromberg A.
        • Lu C.L.
        • Klein F.
        • et al.
        Broadly neutralizing antibodies and viral inducers decrease rebound from HIV-1 latent reservoirs in humanized mice.
        Cell. 2014; 158: 989-999
        • Seung E.
        • Dudek T.E.
        • Allen T.M.
        • Freeman G.J.
        • Luster A.D.
        • Tager A.M.
        PD-1 blockade in chronically HIV-1-infected humanized mice suppresses viral loads.
        PLoS One. 2013; 8: e77780
        • Delaugerre C.
        • Gourlain K.
        • Tubiana R.
        • et al.
        Increase of HIV-1 pro-viral DNA per million peripheral blood mononuclear cells in patients with advanced HIV disease (CD4<200 cells/mm3) receiving interleukin 2 combined with HAART versus HAART alone (ANRS-082 trial).
        Antivir Ther. 2003; 8: 233-237
        • Vandergeeten C.
        • Fromentin R.
        • DaFonseca S.
        • et al.
        Interleukin-7 promotes HIV persistence during antiretroviral therapy.
        Blood. 2013; 121: 4321-4329
        • Hill A.L.
        • Rosenbloom D.I.
        • Fu F.
        • Nowak M.A.
        • Siliciano R.F.
        Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1.
        Proc Natl Acad Sci U S A. 2014; 111: 13475-13480
        • Yukl S.A.
        • Boritz E.
        • Busch M.
        • et al.
        Challenges in detecting HIV persistence during potentially curative interventions: a study of the Berlin patient.
        PLoS Pathog. 2013; 9: e1003347
        • Buzon M.J.
        • Martin-Gayo E.
        • Pereyra F.
        • et al.
        Long-term antiretroviral treatment initiated at primary HIV-1 infection affects the size, composition, and decay kinetics of the reservoir of HIV-1-infected CD4 T cells.
        J Virol. 2014; 88: 10056-10065
        • Ananworanich J.
        • Dube K.
        • Chomont N.
        How does the timing of antiretroviral therapy initiation in acute infection affect HIV reservoirs?.
        Curr Opin HIV AIDS. 2015; 10: 18-28