Journal of Infectious Diseases Advance Access published May 17, 2015
EDITORIAL COMMENTARY
The Remarkable Stability of the Latent Reservoir for HIV-1 in Resting Memory CD4+ T Cells Janet M. Siliciano1 and Robert F. Siliciano1,2 1
Department of Medicine, Johns Hopkins University School of Medicine, and 2Howard Hughes Medical Institute, Baltimore, Maryland
Keywords.
HIV-1; latency; reservoir; resting memory CD4+ T cells; eradication; cure.
Received and accepted 6 April 2015. Correspondence: Janet M. Siliciano, PhD, Johns Hopkins School of Medicine, 733 N Broadway, Miller Research Bldg 871, Baltimore, MD 21205 ([email protected]). The Journal of Infectious Diseases® © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/infdis/jiv219
factors that are recruited to the HIV prompter only after T-cell activation. The latent reservoir for HIV-1 was originally demonstrated using an assay in which resting cells from patients are activated to reverse latency [6]. Viruses released from individual latently infected cells are expanded in culture. This viral outgrowth assay (VOA) was used to demonstrate the remarkable stability of the latent reservoir [7–9]. The half-life of this pool of cells was shown to be 44 months. At this rate of decay, >70 years would be required for a pool of just 106 cells to decay completely [8, 9]. Initial studies of the decay of the latent reservoir were completed in 2003 [9]. Since that time, remarkable advances in ART have taken place, including the introduction of new classes of antiretroviral drugs, such as integrase inhibitors, and the development of simplified regimens in which multiple antiretroviral drugs are combined into a single pill that can be taken once daily [4]. In this context, an extensive and careful study of latent reservoir decay by Crooks et al [10], reported in this issue of the Journal, is of particular interest. The authors have reexamined the stability of the latent reservoir using longitudinal VOAs in a series of 37 patients, some of whom have been receiving treatment for most of the modern ART era. Despite the long duration of treatment in some patients and the changes in ART, the authors found that the decay rate of the latent reservoir is
almost exactly the same as that reported in 2003. The half-life measured by Crooks et al is 43 months [10]. The fact that the decay rate measured in the present study is no different from that measured more than a decade ago confirms that the stability of the latent reservoir is not determined by treatment regimens. As long as the regimen produces a complete or near-complete arrest of new infection events, the decay of the reservoir is determined by the biology of the resting memory T cells that harbor persistent HIV-1. Pharmacodynamic studies indicate that the nonnucleoside reversetranscriptase inhibitors and PIs possess a remarkable potential to inhibit viral replication, a property that reflects an unexpected degree of cooperativity in their dose-response curves [11, 12]. At clinical concentrations, the best PIs can actually produce a 10 billion–fold inhibition of a single round of HIV-1 replication. Thus, even the early combination therapy regimens may have produced complete or near-complete inhibition of new infection events in drug-adherent patients. Subsequent improvements in ART have largely affected tolerability and convenience. Viewed in this light, the finding that the reservoir decay is constant is not surprising. The cures now being routinely achieved with direct-acting antiviral drugs against hepatitis C virus are another reflection of the remarkable ability of certain antiviral drugs to block viral replication. The big difference, of course,
EDITORIAL COMMENTARY
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JID
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Downloaded from http://jid.oxfordjournals.org/ at Sussex Language Institute on August 9, 2015
The modern era of antiretroviral therapy (ART) for human immunodeficiency virus type 1 (HIV-1) infection began in the mid-1990s with the introduction of 2 new classes of antiretroviral drugs, the protease inhibitors (PIs) and the nonnucleoside reverse-transcriptase inhibitors. Combinations consisting of 1 of these drugs along with 2 nucleoside analogue reverse-transcriptase inhibitors rapidly reduced plasma HIV-1 RNA levels to below the limit of detection of clinical assays [1, 2], leading to predictions that continued treatment for 2–3 years could cure the infection [3]. Although it did not prove curative, combination ART became the mainstay of HIV treatment, allowing durable control of viral replication and reversal or prevention of immunodeficiency [4]. A major reason why ART did not prove curative is the persistence of a latent form of the virus in a small population of resting memory CD4+ T cells [5, 6]. In these cells, the viral genome is stably integrated into host cell DNA, but viral genes are not expressed at significant levels in part because of the absence of key host transcription
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EDITORIAL COMMENTARY
without specific interventions to target the reservoir. Since the initial report of the cure of a single patient by a hematopoietic stem cell transplant [22], there has been a dramatic increase in optimism that HIV-1 infection may be curable if the problem of the latent reservoir can be overcome. An important study by Archin et al [23] showed that the reservoir can be perturbed in vivo by a histone deacetylase inhibitor, and many trials of latency reversing agents are now beginning [24, 25]. One critical issue going forward is how to measure the reservoir in these eradication studies. There is no clinical assay for the latent reservoir. The VOA, which has long been regarded as the gold standard, is expensive and time consuming. Because of the low frequency of latently infected cells (mean frequency, 6-fold. They suggest 6-fold as a credible threshold for an intervention-induced decline in the reservoir, although much larger declines may be necessary to produce a substantial
delay in the time to viral rebound after discontinuation of ART [27]. Crooks et al [10] also clarify an important issue related to the decay of the reservoir in patients who start treatment early in the course of infection. Although findings of several studies suggest that early treatment may result in a smaller reservoir, a stable reservoir can be seeded within a matter of days after infection [28] and, in contrast to some previous reports, the authors found no difference in reservoir decay rates between patients starting treatment during acute versus chronic infection. Thus, although early treatment is preferred for many patients, it is unlikely to overcome the problem of the latent reservoir. It is likely that all infected individuals will require interventions directly targeting the reservoir to achieve a cure. Note Potential conflict of interest. Both authors: No potential conflicts of interest. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
References 1. Gulick RM, Mellors JW, Havlir D, et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med 1997; 337: 734–9. 2. Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med 1997; 337:725–33. 3. Perelson AS, Essunger P, Cao Y, et al. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 1997; 387:188–91. 4. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services, 2013. http://Aidsinfo.nih.gov/ contentfiles/lvguidelines/AdultandAdolescent GL.pdf. Accessed 1 April 2015. 5. Chun TW, Finzi D, Margolick J, Chadwick K, Schwartz D, Siliciano RF. In vivo fate of HIV1-infected T cells: quantitative analysis of the
Downloaded from http://jid.oxfordjournals.org/ at Sussex Language Institute on August 9, 2015
is that there is not a latent reservoir for hepatitis C virus. Finding ways to eliminate the latent reservoir for HIV-1 has become a major focus of HIV research. The results reported by Crooks et al [10] highlight the remarkable stability of this reservoir. The stability can be explained by the fact that latent HIV-1 resides predominantly in memory CD4 + T cells [6]. Memory T-cell responses in humans decay very slowly, with a halflife of 8–15 years [13]. This reflects the long-term survival in individual memory T cells as well as the homeostatic proliferation process that preserves immunologic memory to specific pathogens at protective levels for life. Several studies provide evidence for the clonal expansion of populations of HIV-1–infected cells [14–17]. The trace amount of free virus found in the plasma of patients receiving suppressive ART seem to originate from stable reservoirs [18] and is frequently oligoclonal [14, 15], suggesting that this residual viremia may be produced by cells that have undergone clonal expansion after infection. More recently, 2 laboratories have provided direct evidence for clonal expansion of infected cells by demonstrating multiple cells with the same viral integration site [16, 17]. HIV-1 typically integrates into actively expressed genes throughout the genome [19, 20]; thus, each integration event is unique. The repeated detection of identical integration sites suggests that some infected cells can proliferate after infection. A caveat to this notion is that the integration site studies capture only the very ends of the HIV-1 genome. Some findings suggest that most proviruses in resting CD4+ T cells harbor large internal deletions and/or APOBEC3G-mediated hypermutation and are thus not competent for replication [21]. Whether clonal expansion plays a major role in the persistence of cells with replication-competent virus is still a matter of debate. However, regardless of the mechanism of persistence, the study by Crooks et al [10] confirms that the latent reservoir is sufficiently stable to preclude HIV-1 eradication
6.
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9.
10.
12.
13.
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highly active antiretroviral therapy result from two processes: Expression of archival virus and replication of virus. J Virol 2005; 79:9625–34. Bailey JR, Sedaghat AR, Kieffer T, et al. Residual human immunodeficiency virus type 1 viremia in some patients on antiretroviral therapy is dominated by a small number of invariant clones rarely found in circulating CD4+ T cells. J Virol 2006; 80:6441–57. Wagner TA, McLaughlin S, Garg K, et al. HIV latency: proliferation of cells with HIV integrated into cancer genes contributes to persistent infection. Science 2014; 345:570–3. Maldarelli F, Wu X, Su L, et al. HIV latency: specific HIV integration sites are linked to clonal expansion and persistence of infected cells. Science 2014; 345:179–83. Dinoso JB, Kim SY, Wiegand AM, et al. Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc Natl Acad Sci U S A 2009; 106:9403–8. Schroder AR, Shinn P, Chen H, Berry C, Ecker JR, Bushman F. HIV-1 integration in the human genome favors active genes and local hotspots. Cell 2002; 110:521–9. Han Y, Lassen K, Monie D, et al. Resting CD4+ T cells from human immunodeficiency virus type 1 (HIV-1)-infected individuals carry integrated HIV-1 genomes within actively transcribed host genes. J Virol 2004; 78:6122–33. Ho YC, Shan L, Hosmane NN, et al. Replication-competent noninduced proviruses in
22.
23.
24.
25.
26.
27.
28.
the latent reservoir increase barrier to HIV1 cure. Cell 2013; 155:540–51. Hutter G, Nowak D, Mossner M, et al. Longterm control of HIV by CCR5 delta32/ delta32 stem-cell transplantation. N Engl J Med 2009; 360:692–8. Archin NM, Liberty AL, Kashuba AD, et al. Administration of vorinostat disrupts HIV1 latency in patients on antiretroviral therapy. Nature 2012; 487:482–5. Wei DG, Chiang V, Fyne E, et al. Histone deacetylase inhibitor romidepsin induces HIV expression in CD4 T cells from patients on suppressive antiretroviral therapy at concentrations achieved by clinical dosing. PLoS Pathog 2014; 10:e1004071. Spivak AM, Andrade A, Eisele E, et al. A pilot study assessing the safety and latency-reversing activity of disulfiram in HIV-1-infected adults on antiretroviral therapy. Clin Infect Dis 2014; 58:883–90. Eriksson S, Graf EH, Dahl V, et al. Comparative analysis of measures of viral reservoirs in HIV-1 eradication studies. PLoS Pathog 2013; 9:e1003174. 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; 111:13475–80. 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 U S A 1998; 95:8869–73.
EDITORIAL COMMENTARY
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Downloaded from http://jid.oxfordjournals.org/ at Sussex Language Institute on August 9, 2015
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transition to stable latency. Nat Med 1995; 1:1284–90. Chun TW, Carruth L, Finzi D, et al. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 1997; 387:183–8. Finzi D, Hermankova M, Pierson T, et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 1997; 278:1295–300. Finzi D, Blankson J, Siliciano JD, et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med 1999; 5:512–7. Siliciano JD, Kajdas J, Finzi D, et al. Longterm follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med 2003; 9:727–8. Crooks AM, Bateson R, Cope AB, et al. Precise quantitation of the latent HIV-1 reservoir: implications for eradication strategies. J Infect Dis 2015; doi:10.1093/infdis/jiv218. Shen L, Peterson S, Sedaghat AR, et al. Doseresponse curve slope sets class-specific limits on inhibitory potential of anti-HIV drugs. Nat Med 2008; 14:762–6. Jilek BL, Zarr M, Sampah ME, et al. A quantitative basis for antiretroviral therapy for HIV-1 infection. Nat Med 2012; 18:446–51. Hammarlund E, Lewis MW, Hansen SG, et al. Duration of antiviral immunity after smallpox vaccination. Nat Med 2003; 9:1131–7. Tobin NH, Learn GH, Holte SE, et al. Evidence that low-level viremias during effective
EDITORIAL COMMENTARY
The Remarkable Stability of the Latent Reservoir for HIV-1 in Resting Memory CD4+ T Cells Janet M. Siliciano1 and Robert F. Siliciano1,2 1
Department of Medicine, Johns Hopkins University School of Medicine, and 2Howard Hughes Medical Institute, Baltimore, Maryland
Keywords.
HIV-1; latency; reservoir; resting memory CD4+ T cells; eradication; cure.
Received and accepted 6 April 2015. Correspondence: Janet M. Siliciano, PhD, Johns Hopkins School of Medicine, 733 N Broadway, Miller Research Bldg 871, Baltimore, MD 21205 ([email protected]). The Journal of Infectious Diseases® © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/infdis/jiv219
factors that are recruited to the HIV prompter only after T-cell activation. The latent reservoir for HIV-1 was originally demonstrated using an assay in which resting cells from patients are activated to reverse latency [6]. Viruses released from individual latently infected cells are expanded in culture. This viral outgrowth assay (VOA) was used to demonstrate the remarkable stability of the latent reservoir [7–9]. The half-life of this pool of cells was shown to be 44 months. At this rate of decay, >70 years would be required for a pool of just 106 cells to decay completely [8, 9]. Initial studies of the decay of the latent reservoir were completed in 2003 [9]. Since that time, remarkable advances in ART have taken place, including the introduction of new classes of antiretroviral drugs, such as integrase inhibitors, and the development of simplified regimens in which multiple antiretroviral drugs are combined into a single pill that can be taken once daily [4]. In this context, an extensive and careful study of latent reservoir decay by Crooks et al [10], reported in this issue of the Journal, is of particular interest. The authors have reexamined the stability of the latent reservoir using longitudinal VOAs in a series of 37 patients, some of whom have been receiving treatment for most of the modern ART era. Despite the long duration of treatment in some patients and the changes in ART, the authors found that the decay rate of the latent reservoir is
almost exactly the same as that reported in 2003. The half-life measured by Crooks et al is 43 months [10]. The fact that the decay rate measured in the present study is no different from that measured more than a decade ago confirms that the stability of the latent reservoir is not determined by treatment regimens. As long as the regimen produces a complete or near-complete arrest of new infection events, the decay of the reservoir is determined by the biology of the resting memory T cells that harbor persistent HIV-1. Pharmacodynamic studies indicate that the nonnucleoside reversetranscriptase inhibitors and PIs possess a remarkable potential to inhibit viral replication, a property that reflects an unexpected degree of cooperativity in their dose-response curves [11, 12]. At clinical concentrations, the best PIs can actually produce a 10 billion–fold inhibition of a single round of HIV-1 replication. Thus, even the early combination therapy regimens may have produced complete or near-complete inhibition of new infection events in drug-adherent patients. Subsequent improvements in ART have largely affected tolerability and convenience. Viewed in this light, the finding that the reservoir decay is constant is not surprising. The cures now being routinely achieved with direct-acting antiviral drugs against hepatitis C virus are another reflection of the remarkable ability of certain antiviral drugs to block viral replication. The big difference, of course,
EDITORIAL COMMENTARY
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JID
•
1
Downloaded from http://jid.oxfordjournals.org/ at Sussex Language Institute on August 9, 2015
The modern era of antiretroviral therapy (ART) for human immunodeficiency virus type 1 (HIV-1) infection began in the mid-1990s with the introduction of 2 new classes of antiretroviral drugs, the protease inhibitors (PIs) and the nonnucleoside reverse-transcriptase inhibitors. Combinations consisting of 1 of these drugs along with 2 nucleoside analogue reverse-transcriptase inhibitors rapidly reduced plasma HIV-1 RNA levels to below the limit of detection of clinical assays [1, 2], leading to predictions that continued treatment for 2–3 years could cure the infection [3]. Although it did not prove curative, combination ART became the mainstay of HIV treatment, allowing durable control of viral replication and reversal or prevention of immunodeficiency [4]. A major reason why ART did not prove curative is the persistence of a latent form of the virus in a small population of resting memory CD4+ T cells [5, 6]. In these cells, the viral genome is stably integrated into host cell DNA, but viral genes are not expressed at significant levels in part because of the absence of key host transcription
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EDITORIAL COMMENTARY
without specific interventions to target the reservoir. Since the initial report of the cure of a single patient by a hematopoietic stem cell transplant [22], there has been a dramatic increase in optimism that HIV-1 infection may be curable if the problem of the latent reservoir can be overcome. An important study by Archin et al [23] showed that the reservoir can be perturbed in vivo by a histone deacetylase inhibitor, and many trials of latency reversing agents are now beginning [24, 25]. One critical issue going forward is how to measure the reservoir in these eradication studies. There is no clinical assay for the latent reservoir. The VOA, which has long been regarded as the gold standard, is expensive and time consuming. Because of the low frequency of latently infected cells (mean frequency, 6-fold. They suggest 6-fold as a credible threshold for an intervention-induced decline in the reservoir, although much larger declines may be necessary to produce a substantial
delay in the time to viral rebound after discontinuation of ART [27]. Crooks et al [10] also clarify an important issue related to the decay of the reservoir in patients who start treatment early in the course of infection. Although findings of several studies suggest that early treatment may result in a smaller reservoir, a stable reservoir can be seeded within a matter of days after infection [28] and, in contrast to some previous reports, the authors found no difference in reservoir decay rates between patients starting treatment during acute versus chronic infection. Thus, although early treatment is preferred for many patients, it is unlikely to overcome the problem of the latent reservoir. It is likely that all infected individuals will require interventions directly targeting the reservoir to achieve a cure. Note Potential conflict of interest. Both authors: No potential conflicts of interest. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
References 1. Gulick RM, Mellors JW, Havlir D, et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med 1997; 337: 734–9. 2. Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med 1997; 337:725–33. 3. Perelson AS, Essunger P, Cao Y, et al. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 1997; 387:188–91. 4. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services, 2013. http://Aidsinfo.nih.gov/ contentfiles/lvguidelines/AdultandAdolescent GL.pdf. Accessed 1 April 2015. 5. Chun TW, Finzi D, Margolick J, Chadwick K, Schwartz D, Siliciano RF. In vivo fate of HIV1-infected T cells: quantitative analysis of the
Downloaded from http://jid.oxfordjournals.org/ at Sussex Language Institute on August 9, 2015
is that there is not a latent reservoir for hepatitis C virus. Finding ways to eliminate the latent reservoir for HIV-1 has become a major focus of HIV research. The results reported by Crooks et al [10] highlight the remarkable stability of this reservoir. The stability can be explained by the fact that latent HIV-1 resides predominantly in memory CD4 + T cells [6]. Memory T-cell responses in humans decay very slowly, with a halflife of 8–15 years [13]. This reflects the long-term survival in individual memory T cells as well as the homeostatic proliferation process that preserves immunologic memory to specific pathogens at protective levels for life. Several studies provide evidence for the clonal expansion of populations of HIV-1–infected cells [14–17]. The trace amount of free virus found in the plasma of patients receiving suppressive ART seem to originate from stable reservoirs [18] and is frequently oligoclonal [14, 15], suggesting that this residual viremia may be produced by cells that have undergone clonal expansion after infection. More recently, 2 laboratories have provided direct evidence for clonal expansion of infected cells by demonstrating multiple cells with the same viral integration site [16, 17]. HIV-1 typically integrates into actively expressed genes throughout the genome [19, 20]; thus, each integration event is unique. The repeated detection of identical integration sites suggests that some infected cells can proliferate after infection. A caveat to this notion is that the integration site studies capture only the very ends of the HIV-1 genome. Some findings suggest that most proviruses in resting CD4+ T cells harbor large internal deletions and/or APOBEC3G-mediated hypermutation and are thus not competent for replication [21]. Whether clonal expansion plays a major role in the persistence of cells with replication-competent virus is still a matter of debate. However, regardless of the mechanism of persistence, the study by Crooks et al [10] confirms that the latent reservoir is sufficiently stable to preclude HIV-1 eradication
6.
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highly active antiretroviral therapy result from two processes: Expression of archival virus and replication of virus. J Virol 2005; 79:9625–34. Bailey JR, Sedaghat AR, Kieffer T, et al. Residual human immunodeficiency virus type 1 viremia in some patients on antiretroviral therapy is dominated by a small number of invariant clones rarely found in circulating CD4+ T cells. J Virol 2006; 80:6441–57. Wagner TA, McLaughlin S, Garg K, et al. HIV latency: proliferation of cells with HIV integrated into cancer genes contributes to persistent infection. Science 2014; 345:570–3. Maldarelli F, Wu X, Su L, et al. HIV latency: specific HIV integration sites are linked to clonal expansion and persistence of infected cells. Science 2014; 345:179–83. Dinoso JB, Kim SY, Wiegand AM, et al. Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc Natl Acad Sci U S A 2009; 106:9403–8. Schroder AR, Shinn P, Chen H, Berry C, Ecker JR, Bushman F. HIV-1 integration in the human genome favors active genes and local hotspots. Cell 2002; 110:521–9. Han Y, Lassen K, Monie D, et al. Resting CD4+ T cells from human immunodeficiency virus type 1 (HIV-1)-infected individuals carry integrated HIV-1 genomes within actively transcribed host genes. J Virol 2004; 78:6122–33. Ho YC, Shan L, Hosmane NN, et al. Replication-competent noninduced proviruses in
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28.
the latent reservoir increase barrier to HIV1 cure. Cell 2013; 155:540–51. Hutter G, Nowak D, Mossner M, et al. Longterm control of HIV by CCR5 delta32/ delta32 stem-cell transplantation. N Engl J Med 2009; 360:692–8. Archin NM, Liberty AL, Kashuba AD, et al. Administration of vorinostat disrupts HIV1 latency in patients on antiretroviral therapy. Nature 2012; 487:482–5. Wei DG, Chiang V, Fyne E, et al. Histone deacetylase inhibitor romidepsin induces HIV expression in CD4 T cells from patients on suppressive antiretroviral therapy at concentrations achieved by clinical dosing. PLoS Pathog 2014; 10:e1004071. Spivak AM, Andrade A, Eisele E, et al. A pilot study assessing the safety and latency-reversing activity of disulfiram in HIV-1-infected adults on antiretroviral therapy. Clin Infect Dis 2014; 58:883–90. Eriksson S, Graf EH, Dahl V, et al. Comparative analysis of measures of viral reservoirs in HIV-1 eradication studies. PLoS Pathog 2013; 9:e1003174. 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; 111:13475–80. 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 U S A 1998; 95:8869–73.
EDITORIAL COMMENTARY
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JID
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Downloaded from http://jid.oxfordjournals.org/ at Sussex Language Institute on August 9, 2015
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transition to stable latency. Nat Med 1995; 1:1284–90. Chun TW, Carruth L, Finzi D, et al. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 1997; 387:183–8. Finzi D, Hermankova M, Pierson T, et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 1997; 278:1295–300. Finzi D, Blankson J, Siliciano JD, et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med 1999; 5:512–7. Siliciano JD, Kajdas J, Finzi D, et al. Longterm follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med 2003; 9:727–8. Crooks AM, Bateson R, Cope AB, et al. Precise quantitation of the latent HIV-1 reservoir: implications for eradication strategies. J Infect Dis 2015; doi:10.1093/infdis/jiv218. Shen L, Peterson S, Sedaghat AR, et al. Doseresponse curve slope sets class-specific limits on inhibitory potential of anti-HIV drugs. Nat Med 2008; 14:762–6. Jilek BL, Zarr M, Sampah ME, et al. A quantitative basis for antiretroviral therapy for HIV-1 infection. Nat Med 2012; 18:446–51. Hammarlund E, Lewis MW, Hansen SG, et al. Duration of antiviral immunity after smallpox vaccination. Nat Med 2003; 9:1131–7. Tobin NH, Learn GH, Holte SE, et al. Evidence that low-level viremias during effective
