|Year : 2017 | Volume
| Issue : 2 | Page : 224-230
Factors Associated with the Size of HIV DNA Reservoir
Ni-Dan Wang, Tai-Sheng Li
Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
|Date of Submission||09-Aug-2016|
|Date of Web Publication||10-Jan-2017|
Prof. Tai-Sheng Li
Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730
Source of Support: None, Conflict of Interest: None
Objective: To review the recent literatures related to the factors associated with the size of the HIV reservoir and their clinical significance.
Data Sources: Literatures related to the size of HIV DNA was collected from PubMed published from 1999 to June 2016.
Study Selection: All relevant articles on the HIV DNA and reservoir were collected and reviewed, with no limitation of study design.
Results: The composition and development of the HIV-1 DNA reservoir in either treated or untreated patients is determined by integrated mechanism comprising viral characteristics, immune system, and treatment strategies. The HIV DNA reservoir is a combination of latency and activity. The residual viremia from the stochastic activation of the reservoir acts as the fuse, continuing to stimulate the immune system to maintain the activated microenvironment for the rebound of competent virus once treatment with antiretroviral therapy is discontinued.
Conclusion: The size of the HIV-1 DNA pool and its composition has great significance in clinical treatment and disease progression.
Keywords: Antiretroviral Treatment; HIV-1 DNA; Immune Activation; Latent Reservoir; Residual Viremia
|How to cite this article:|
Wang ND, Li TS. Factors Associated with the Size of HIV DNA Reservoir. Chin Med J 2017;130:224-30
| Introduction|| |
The rapid development of novel antiretroviral treatments has increased adherence to drug regimens and reduced the related toxicity,,, which has driven scientists to be interested in an HIV functional cure. Although many studies have tried to achieve functional cure, the persistence of the HIV reservoir is the main obstacle for the realization of this goal. From biological aspect, HIV, as a retrovirus, has two typical steps in its viral replication cycle. The first step is reverse transcription, and the second is integration. HIV DNA exists in the body in two major forms: integrated and unintegrated. Precise assays to directly quantify cell-associated integrated and unintegrated HIV DNA have facilitated the close monitoring of the capacity of HIV virus proliferation even when the virus is suppressed.,,, The total HIV DNA level is an independent predictor of disease progression for primary HIV infection without treatment., Accumulating research suggests that even with the efficacy of current antiretroviral medicines, it is difficult to eradicate or even efficiently reduce HIV DNA to a very low level, especially in chronically infected patients with high HIV DNA at baseline. The mechanisms of HIV persistence in the reservoir during successful antiretroviral therapy (ART) have been widely reported, including residual viremia, cell-to-cell transmission, and clonal proliferation of infected CD4+ T-cells.,,
Many factors influence the size of the HIV-1 DNA pool and its decay. The size of the HIV-1 DNA pool and its composition has great significance in clinical diagnosis and disease progression. Although there are many excellent reviews on the HIV-1 reservoir, most focus on one aspect at the basic research level.,,,,,, Here, we described the relevant factors in a simplified way, focusing on the clinical research to make the information more intuitive to the clinician.
| Viral Characteristics|| |
The viral replicative capacity represents the virulence and predicts the speed of disease progress. The virulence of HIV variants is closely related with the viral set point and the decline of CD4+ T-cells., Compared to the virus in the plasma which is more likely to represent recently produced viral particles, HIV DNA in the tissue, especially in the lymph node, often represents the sequences from the original ancestral virus. However, considering the available sample resources, most quantification assays detect circular cell-associated HIV DNA in the blood. In the early stage of infection, unintegrated HIV DNA represents a large proportion of the total DNA. The level of unintegrated HIV DNA is associated with the efficiency of viral replication. Thus, in most studies, the viral load is positively correlated with the quantity of HIV DNA. Just like the set point viral load, the HIV DNA tends to remain at a stable level after peak viremia without ART intervention. Although many factors influence the set point viral load, with regard to viral characteristics, the number of transmitted viruses has been a recent focus of extensive research. Considering the biological characteristics of retroviruses, which undergo reverse transcription and then integration, there is no reason to rule out the possibility that the number of transmitted founder viruses has no relationship with the overall quantity of HIV DNA. More studies are needed to determine the relationship between the HIV DNA baseline level and the characteristics of the virus.
| Host Immune Background|| |
In addition to virological factors, the host immune background is also associated with the clinical outcome. Sexual transmission pairs or mother-child pairs with known transmission relationships provide data about the significant role played by human leukocyte antigen (HLA) and the natural immune system in the control of disease progression.,,,,,,, Under a similar immune background, the ratio and the count of T-cell subsets are strongly associated with inflammation and HIV persistence.,, Although there have not been many reports about the relationship between the size of HIV reservoir and HLA genotype, elite controllers with a protective HLA type tend to have a lower HIV DNA level and are more likely to have powerful immune responses. The initial HIV DNA baseline can be controlled by the breadth and magnitude of HIV-1-specific CD4+ T-cells.,, This is also the reason why long-term nonprogressors have very low levels of HIV DNA, outside of that from defective virus at the beginning of infection., Antibody-dependent cell-mediated cytotoxicity is another factor that reduces or controls the quantity of cell-associated HIV DNA. The association between the HLA polymorphisms and HIV reservoir is not fully understood.,, More research about this field can provide information related to the mechanism of natural control and identify potential cytotoxic T-lymphocyte epitopes for vaccine design.
| Coinfection|| |
HIV-1-infected patients are capable of being coinfected with other viral and bacterial pathogens. Strong evidence has demonstrated that asymptomatic replication of human herpesvirus can mediate immune activation and is associated with higher levels of HIV DNA during ART.,, In addition, the presence of cytomegalovirus is positively correlated with the HIV DNA level in both treated and untreated individuals. The probable reason for these might be as follows: The development of more activated, antigen-specific CD4+ T-cells provides new target cells for reseeding the HIV reservoir. Increases in the levels of cytokines and chemokines would also stimulate inflammation and immune activation. The persistence of other viruses changes the immune environment and allows the HIV reservoir to become more diverse, which ultimately influences its decay.
| Impact of Different Combination Antiretroviral Therapy Strategies and Stimulating Agents on the HIV DNA|| |
Compared to early treatment at the acute stage, it is difficult to further reduce the reservoir of chronically infected patients with long-term treatment. Most intensified treatments have no impact on the HIV-1 reservoir compared to standard triple-drug therapy.,, A switch to monotherapy from a standard regime in virally suppressed individuals has been investigated in several studies. Although there is no difference in viral control or CD4 count and even an improvement in lipometabolism with this strategy, long-term studies of the changes in the homeostasis of HIV-1 reservoir are needed., Furthermore, new antiretroviral agents are urgently needed to act directly on the HIV-1 reservoir. Among several strategies, "shock and kill" has been an actively studied method to eradicate the reservoir. However, the results have not been optimal with either master transcription factors or interleukins as the reactivating agent's targets.,, However, new evidence has demonstrated the persistence of activated subspecies of HIV DNA after long-term effective ART, which might suggest the use of more caution with this strategy.,,
| Residual Viremia|| |
The detection limit of clinical HIV assays is 50 copies/ml of plasma. With the advent of highly sensitive real-time polymerase chain reaction, which is capable of detecting single copies of HIV RNA in the plasma, many studies have demonstrated the presence of residual viremia in some successfully suppressed individuals after many years of ART., The copy number of residual viremia during the follow-up was shown in some studies to be positively associated with the baseline level of HIV DNA and RNA. In one cross-sectional cohort study, 63% (80/127) of participants receiving ART for a median of 6.3 years had detectable viremia that was positively correlated with the level of HIV DNA present in the individual. The mechanism of the existence of residual viremia is not clear. Drug-resistant variants might be one reason, particularly considering the low penetrance of the ART drugs in the lymphoid tissue., In most cases, the role of residual viremia has not been completely identified., The persistent low level of residual viremia caused by the activated latent reservoir has a role in replenishing the pool of HIV DNA. The fact that HIV-specific CD4+ T-cells are preferentially infected by HIV-1 at all stages of disease suggests the possibility that residual viremia continues to mediate the infection or stimulation of activated CD4+ T-cells even under effective ART. More studies are needed to compare the productive capacity of residual viremia among patients with different reservoir sizes.
| Immune Activation|| |
Although the immune activation phenotype is diverse, the frequency of T-cells expressing HLA-DR and CD38 has often been used. Based on the recent evidence, the total HIV DNA has a closer relationship with the number of HLA-DR + CD38 - cells containing the integrated HIV DNA than with the number of CD38+ memory T-cells. Like the dynamic decay of HIV DNA with ART, the level of certain immune activation biomarkers tended to be stable after 1 year of viral suppression. No matter the reason for the systemic immune activation during HIV-1 infection, it is an important factor associated with the size of the HIV reservoir in a long-term plasma-suppressed cohort lacking any viral blips under ART., A consistent positive relationship has been demonstrated between T-cell immune activation and cell-associated DNA and RNA. There is a possibility that activated immune cells stimulate the proliferation of the HIV reservoir. However, Some elite controllers exhibit spontaneous viral suppression and a low level of HIV DNA but also have a high level of inflammatory markers and a high risk of clinical cardiovascular disease compared to those well-controlled on ART. Based on recent evidence, immune activation tends to be a sign of the effect of the immune response on the HIV reservoir besides a direct influence. The relationship among residual viremia, cellular HIV DNA, and immune activation remains further study.,,
| Diversity of the HIV-1 Reservoir|| |
Recent developments in technology and theory have increased our knowledge of the diversity of the HIV-1 reservoir.,, The half-life of HIV-1 DNA in different subsets of memory T-cell populations is different; it is 277, 144, 133, and 88 months for stem-like, central-memory, transitional-memory, and effector-memory T-cells, respectively., Some special cell subsets, such as Th17 and T follicular helper cells, play an important role in the persistence of the HIV-1 reservoir in both untreated individuals and those receiving long-term treatment., Not only is the cell subset correlated with the rate of decay of the HIV-1 reservoir, but also the tissue compartment also influences the destiny of tissue-resident HIV-1-infected memory T-cells., The tissues are the largest reservoir for HIV; thus, the mechanism of HIV persistence and changes in HIV DNA subspecies during ART needs to be further evaluated using nonblood samples. The limitations of HIV DNA detection in peripheral blood samples are made even more clear by the continuous reduction of Th17 cells in partial gut tissue from successfully treated individuals., More studies are needed to investigate the cell composition and interaction of the HIV-1 reservoir in long-term successfully treated individuals. The results from these studies will improve the design of strategies to control homeostatic proliferation and stability.
| Conclusions|| |
The composition and development of the HIV-1 DNA reservoir either in treated or untreated patients is determined by integrated mechanism comprising viral characteristics, immune system, and treatment strategies [Figure 1]. The immune system as a network might be altered in HIV infected patients receiving treatment compared to healthy controls. A subtle balance between replication and homeostasis is required to keep the HIV reservoir at a constant level after the depletion of the actively replicating virus by ART. During the period of long-term suppression of replication, a lack of a robust HIV-specific CD4+ T-cell response to eliminate the residual reservoir in circulating blood cells and tissue means that the HIV-1 reservoir remains a ticking time bomb., The residual viremia from the stochastic activation of the reservoir acts as the fuse, continuing to stimulate the immune system to maintain the activated microenvironment for the rebound of competent virus once treatment with ART is discontinued.,, An optimized strategy should be developed through a combination of antiretroviral medicine, specific immunity, and latent activation agents.
|Figure 1: The composition and development of the HIV-1 DNA reservoir either in treated or untreated patients is determined by integrated mechanism comprising viral characteristics, immune system, and drugs|
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In summary, the size of the HIV-1 DNA pool and its composition has great significance in clinical treatment and disease progression.
Financial support and sponsorship
This work was supported by grants from the National Key Technologies R&D Program for the 11th 5-year Plan (No. 2008ZX10001-006) and the 12th 5-year Plan (No. 2012 ZX10001-003).
Conflicts of interest
There are no conflicts of interest.
| References|| |
De Clercq E. Tenofovir alafenamide (TAF) as the successor of tenofovir disoproxil fumarate (TDF). Biochem Pharmacol 2016;119:1-7. doi: 10.1016/j.bcp.2016.04.015.
Swartz JE, Vandekerckhove L, Ammerlaan H, de Vries AC, Begovac J, Bierman WF, et al.
Efficacy of tenofovir and efavirenz in combination with lamivudine or emtricitabine in antiretroviral-naive patients in Europe. J Antimicrob Chemother 2015;70:1850-7. doi: 10.1093/jac/dkv033.
Li T, Guo F, Li Y, Zhang C, Han Y, Lye W, et al
. An antiretroviral regimen containing 6 months of stavudine followed by long-term zidovudine for first-line HIV therapy is optimal in resource-limited settings: A prospective, multicenter study in China. Chin Med J 2014;127:59-65. doi: 10.3760/cma.j.issn.0366-6999.20132557.
Kimata JT, Rice AP, Wang J. Challenges and strategies for the eradication of the HIV reservoir. Curr Opin Immunol 2016;42:65-70. doi: 10.1016/j.coi.2016.05.015.
Craigie R, Bushman FD. HIV DNA integration. Cold Spring Harb Perspect Med 2012;2:a006890. doi: 10.1101/cshperspect.a006890.
Casabianca A, Orlandi C, Canovari B, Scotti M, Acetoso M, Valentini M, et al.
A real time PCR platform for the simultaneous quantification of total and extrachromosomal HIV DNA forms in blood of HIV-1 infected patients. PLoS One 2014;9:e111919. doi: 10.1371/journal.pone.0111919.
Kim M, Siliciano RF. Reservoir expansion by T-cell proliferation may be another barrier to curing HIV infection. Proc Natl Acad Sci U S A 2016;113:1692-4. doi: 10.1073/pnas.1600097113.
von Stockenstrom S, Odevall L, Lee E, Sinclair E, Bacchetti P, Killian M, et al.
Longitudinal genetic characterization reveals that cell proliferation maintains a persistent HIV type 1 DNA pool during effective HIV therapy. J Infect Dis 2015;212:596-607. doi: 10.1093/infdis/jiv092.
McGary CS, Cervasi B, Chahroudi A, Micci L, Taaffe J, Meeker T, et al.
Increased stability and limited proliferation of CD4+ central memory T cells differentiate nonprogressive simian immunodeficiency virus (SIV) infection of sooty mangabeys from progressive SIV infection of rhesus macaques. J Virol 2014;88:4533-42. doi: 10.1128/JVI.03515-13.
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;15:893-900. doi: 10.1038/nm.1972.
Kostrikis LG, Touloumi G, Karanicolas R, Pantazis N, Anastassopoulou C, Karafoulidou A, et al
. Quantitation of human immunodeficiency virus type 1 DNA forms with the second template switch in peripheral blood cells predicts disease progression independently of plasma RNA load. J Virol 2002;76:10099-108. doi: 10.1128/JVI.76.20.10099-10108.2002.
Goujard C, Bonarek M, Meyer L, Bonnet F, Chaix ML, Deveau C, et al.
CD4 cell count and HIV DNA level are independent predictors of disease progression after primary HIV type 1 infection in untreated patients. Clin Infect Dis 2006;42:709-15. doi: 10.1086/500213.
Besson GJ, Lalama CM, Bosch RJ, Gandhi RT, Bedison MA, Aga E, et al.
HIV-1 DNA decay dynamics in blood during more than a decade of suppressive antiretroviral therapy. Clin Infect Dis 2014;59:1312-21. doi: 10.1093/cid/ciu585.
Buzón MJ, Massanella M, Llibre JM, Esteve A, Dahl V, Puertas MC, et al.
HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects. Nat Med 2010;16:460-5. doi: 10.1038/nm.2111.
Chun TW, Nickle DC, Justement JS, Large D, Semerjian A, Curlin ME, et al.
HIV-infected individuals receiving effective antiviral therapy for extended periods of time continually replenish their viral reservoir. J Clin Invest 2005;115:3250-5. doi: 10.1172/JCI26197.
Wong JK, Yukl SA. Tissue reservoirs of HIV. Curr Opin HIV AIDS 2016;11:362-70. doi: 10.1097/coh.0000000000000293.
Sacha JB, Ndhlovu LC. Strategies to target non-T-cell HIV reservoirs. Curr Opin HIV AIDS 2016;11:376-82. doi: 10.1097/coh. 0000000000000283.
Lorenzo-Redondo R, Fryer HR, Bedford T, Kim EY, Archer J, Kosakovsky Pond SL, et al.
Persistent HIV-1 replication maintains the tissue reservoir during therapy. Nature 2016;530:51-6. doi: 10.1038/nature16933.
Lee GQ, Lichterfeld M. Diversity of HIV-1 reservoirs in CD4+ T-cell subpopulations. Curr Opin HIV AIDS 2016;11:383-7. doi: 10.1097/COH.0000000000000281.
Churchill MJ, Deeks SG, Margolis DM, Siliciano RF, Swanstrom R. HIV reservoirs: What, where and how to target them. Nat Rev Microbiol 2016;14:55-60. doi: 10.1038/nrmicro.2015.5.
Barton K, Winckelmann A, Palmer S. HIV-1 reservoirs during suppressive therapy. Trends Microbiol 2016;24:345-55. doi: 10.1016/j.tim.2016.01.006.
Prince JL, Claiborne DT, Carlson JM, Schaefer M, Yu T, Lahki S, et al.
Role of transmitted Gag CTL polymorphisms in defining replicative capacity and early HIV-1 pathogenesis. PLoS Pathog 2012;8:e1003041. doi: 10.1371/journal.ppat.1003041.
Goepfert PA, Lumm W, Farmer P, Matthews P, Prendergast A, Carlson JM, et al.
Transmission of HIV-1 Gag immune escape mutations is associated with reduced viral load in linked recipients. J Exp Med 2008;205:1009-17. doi: 10.1084/jem.20072457.
Avettand-Fenoel V, Hocqueloux L, Müller-Trutwin M, Prazuck T, Melard A, Chaix ML, et al.
Greater diversity of HIV DNA variants in the rectum compared to variants in the blood in patients without HAART. J Med Virol 2011;83:1499-507. doi: 10.1002/jmv.22132.
Mexas AM, Graf EH, Pace MJ, Yu JJ, Papasavvas E, Azzoni L, et al.
Concurrent measures of total and integrated HIV DNA monitor reservoirs and ongoing replication in eradication trials. AIDS 2012;26:2295-306. doi: 10.1097/QAD.0b013e32835a5c2f.
Janes H, Herbeck JT, Tovanabutra S, Thomas R, Frahm N, Duerr A, et al.
HIV-1 infections with multiple founders are associated with higher viral loads than infections with single founders. Nat Med 2015;21:1139-41. doi: 10.1038/nm.3932.
Claiborne DT, Prince JL, Scully E, Macharia G, Micci L, Lawson B, et al.
Replicative fitness of transmitted HIV-1 drives acute immune activation, proviral load in memory CD4 T cells, and disease progression. Proc Natl Acad Sci U S A 2015;112:E1480-9. doi: 10.1073/pnas.1421607112.
Adland E, Paioni P, Thobakgale C, Laker L, Mori L, Muenchhoff M, et al.
Discordant impact of HLA on viral replicative capacity and disease progression in pediatric and adult HIV infection. PLoS Pathog 2015;11:e1004954. doi: 10.1371/journal.ppat.1004954.
Costello C, Tang J, Rivers C, Karita E, Meizen-Derr J, Allen S, et al
. HLA-BFNx015703 independently associated with slower HIV-1 disease progression in Rwandan women. AIDS 1999;13:1990-1.
Carlson JM, Listgarten J, Pfeifer N, Tan V, Kadie C, Walker BD, et al.
Widespread impact of HLA restriction on immune control and escape pathways of HIV-1. J Virol 2012;86:5230-43. doi: 10.1128/JVI.06728-11.
Schneidewind A, Brockman MA, Yang R, Adam RI, Li B, Le Gall S, et al.
Escape from the dominant HLA-B27-restricted cytotoxic T-lymphocyte response in Gag is associated with a dramatic reduction in human immunodeficiency virus type 1 replication. J Virol 2007;81:12382-93. doi: 10.1128/JVI.01543-07.
Matthews PC, Prendergast A, Leslie A, Crawford H, Payne R, Rousseau C, et al.
Central role of reverting mutations in HLA associations with human immunodeficiency virus set point. J Virol 2008;82:8548-59. doi: 10.1128/JVI.00580-08.
Crawford H, Lumm W, Leslie A, Schaefer M, Boeras D, Prado JG, et al.
Evolution of HLA-BFNx015703 HIV-1 escape mutations in HLA-BFNx015703-positive individuals and their transmission recipients. J Exp Med 2009;206:909-21. doi: 10.1084/jem.20081984.
Thobakgale CF, Prendergast A, Crawford H, Mkhwanazi N, Ramduth D, Reddy S, et al.
Impact of HLA in mother and child on disease progression of pediatric human immunodeficiency virus type 1 infection. J Virol 2009;83:10234-44. doi: 10.1128/JVI.00921-09.
Brener J, Gall A, Batorsky R, Riddell L, Buus S, Leitman E, et al.
Disease progression despite protective HLA expression in an HIV-infected transmission pair. Retrovirology 2015;12:55. doi: 10.1186/s12977-015-0179-z.
Ryan ES, Micci L, Fromentin R, Paganini S, McGary CS, Easley K, et al.
Loss of function of intestinal IL-17 and IL-22 producing cells contributes to inflammation and viral persistence in SIV-infected rhesus macaques. PLoS Pathog 2016;12:e1005412. doi: 10.1371/journal.ppat.1005412.
Eller MA, Goonetilleke N, Tassaneetrithep B, Eller LA, Costanzo MC, Johnson S, et al.
Expansion of inefficient HIV-specific CD8+ T cells during acute infection. J Virol 2016;90:4005-16. doi: 10.1128/JVI.02785-15.
Thørner LW, Erikstrup C, Harritshøj LH, Larsen MH, Kronborg G, Pedersen C, et al.
Impact of polymorphisms in the HCP5 and HLA-C, and ZNRD1 genes on HIV viral load. Infect Genet Evol 2016;41:185-90. doi: 10.1016/j.meegid.2016.03.037.
Crowell TA, Hatano H. Clinical outcomes and antiretroviral therapy in ′elite′ controllers: A review of the literature. J Virus Erad 2015;1:72-77.
Norris PJ, Moffett HF, Yang OO, Kaufmann DE, Clark MJ, Addo MM, et al.
Beyond help: Direct effector functions of human immunodeficiency virus type 1-specific CD4(+) T cells. J Virol 2004;78:8844-51. doi: 10.1128/JVI.78.16.8844-8851.2004.
Soghoian DZ, Streeck H. Cytolytic CD4(+) T cells in viral immunity. Expert Rev Vaccines 2010;9:1453-63. doi: 10.1586/erv.10.132.
Soghoian DZ, Jessen H, Flanders M, Sierra-Davidson K, Cutler S, Pertel T, et al.
HIV-specific cytolytic CD4 T cell responses during acute HIV infection predict disease outcome. Sci Transl Med 2012;4:123ra25. doi: 10.1126/scitranslmed.3003165.
Ranasinghe S, Flanders M, Cutler S, Soghoian DZ, Ghebremichael M, Davis I, et al.
HIV-specific CD4 T cell responses to different viral proteins have discordant associations with viral load and clinical outcome. J Virol 2012;86:277-83. doi: 10.1128/JVI.05577-11.
Ramduth D, Day CL, Thobakgale CF, Mkhwanazi NP, de Pierres C, Reddy S, et al.
Immunodominant HIV-1 Cd4+ T cell epitopes in chronic untreated clade C HIV-1 infection. PLoS One 2009;4:e5013. doi: 10.1371/journal.pone.0005013.
von Bredow B, Arias JF, Heyer LN, Moldt B, Le K, Robinson JE, et al.
Comparison of antibody-dependent cell-mediated cytotoxicity and virus neutralization by HIV-1 Env-specific monoclonal antibodies. J Virol 2016;90:6127-39. doi: 10.1128/jvi.00347-16.
Koofhethile CK, Ndhlovu ZM, Thobakgale-Tshabalala C, Prado JG, Ismail N, Mncube Z, et al.
CD8 T Cell breadth and ex vivo
virus inhibition capacity distinguish between viremic controllers with and without protective HLA class I alleles. J Virol 2016;90:6818-31. doi: 10.1128/jvi.00276-16.
Zhang H, Han X, Zhao B, An M, Wang Z, Jiang F, et al.
Multilayered HIV-1 gag-specific T-cell responses contribute to slow progression in HLA-AFNx0130-BFNx0113-CFNx0106-positive patients. AIDS 2015;29:993-1002. doi: 10.1097/QAD.0000000000000652.
Kang W, Zhu W, Li Y, Jiao Y, Zhuang Y, Xie Y, et al.
Analysis of HIV-1c-specific CTL responses with HIV-1 reservoir size and forms. Viral Immunol 2016;29:184-91. doi: 10.1089/vim.2015.0057.
Li YJ, Wang HL, Li TS. Hepatitis B virus/human immunodeficiency virus coinfection: Interaction among human immunodeficiency virus infection, chronic hepatitis B virus infection, and host immunity. Chin Med J 2012;125:2371-7. doi: 10.3760/cma.j.issn.0366-6999.2012.13.023.
Gianella S, Massanella M, Wertheim JO, Smith DM. The sordid affair between human herpesvirus and HIV. J Infect Dis 2015;212:845-52. doi: 10.1093/infdis/jiv148.
Gianella S, Massanella M, Richman DD, Little SJ, Spina CA, Vargas MV, et al.
Cytomegalovirus replication in semen is associated with higher levels of proviral HIV DNA and CD4+ T cell activation during antiretroviral treatment. J Virol 2014;88:7818-27. doi: 10.1128/jvi.00831-14.
Gianella S, Anderson CM, Var SR, Oliveira MF, Lada SM, Vargas MV, et al.
Replication of human herpesviruses is associated with higher HIV DNA levels during antiretroviral therapy started at early phases of HIV infection. J Virol 2016;90:3944-52. doi: 10.1128/jvi.02638-15.
Sylwester AW, Mitchell BL, Edgar JB, Taormina C, Pelte C, Ruchti F, et al.
Broadly targeted human cytomegalovirus-specific CD4 and CD8 T cells dominate the memory compartments of exposed subjects. J Exp Med 2005;202:673-85. doi: 10.1084/jem.20050882.
Ostrowski M, Benko E, Yue FY, Kim CJ, Huibner S, Lee T, et al.
Intensifying Antiretroviral therapy with raltegravir and maraviroc during early human immunodeficiency virus (HIV) infection does not accelerate HIV reservoir reduction. Open Forum Infect Dis 2015;2:ofv138. doi: 10.1093/ofid/ofv138.
Chéret A, Nembot G, Mélard A, Lascoux C, Slama L, Miailhes P, et al.
Intensive five-drug antiretroviral therapy regimen versus standard triple-drug therapy during primary HIV-1 infection (OPTIPRIM-ANRS 147): A randomised, open-label, phase 3 trial. Lancet Infect Dis 2015;15:387-96. doi: 10.1016/s1473-3099(15)70021-6.
Katlama C, Lambert-Niclot S, Assoumou L, Papagno L, Lecardonnel F, Zoorob R, et al.
Treatment intensification followed by interleukin-7 reactivates HIV without reducing total HIV DNA: A randomized trial. AIDS 2016;30:221-30. doi: 10.1097/QAD.0000000000000894.
Rojas J, Blanco JL, Marcos MA, Lonca M, Tricas A, Moreno L, et al.
Dolutegravir monotherapy in HIV-infected patients with sustained viral suppression. J Antimicrob Chemother 2016;71:1975-81. doi: 10.1093/jac/dkw078.
Tiraboschi J, Hamzah L, Teague A, Kulasegaram R, Post F, Jendruleck I, et al.
The impact of switching from Atripla to darunavir/ritonavir monotherapy on neurocognition, quality of life, and sleep: Results from a randomized controlled study. AIDS Res Hum Retroviruses 2016;32(12):1198-1201. doi: 10.1089/aid. 2015.0263.
Mpendo J, Mutua G, Nyombayire J, Ingabire R, Nanvubya A, Anzala O, et al.
A phase i double blind, placebo-controlled, randomized study of the safety and immunogenicity of electroporated HIV DNA with or without interleukin 12 in prime-boost combinations with an Ad35 HIV vaccine in healthy HIV-seronegative African adults. PLoS One 2015;10:e0134287. doi: 10.1371/journal.pone. 0134287.
Spivak AM, Planelles V. HIV-1 eradication: Early trials (and tribulations). Trends Mol Med 2016;22:10-27. doi: 10.1016/j.molmed.2015.11.004.
Cummins NW, Sainski AM, Dai H, Natesampillai S, Pang YP, Bren GD, et al.
Prime, shock, and kill: Priming CD4 T cells from HIV patients with a BCL-2 antagonist before HIV reactivation reduces HIV reservoir size. J Virol 2016;90:4032-48. doi: 10.1128/JVI.03179-15.
Jones RB, Mueller S, O′Connor R, Rimpel K, Sloan DD, Karel D, et al.
A subset of latency-reversing agents expose HIV-infected resting CD4+ T-cells to recognition by cytotoxic T-lymphocytes. PLoS Pathog 2016;12:e1005545. doi: 10.1371/journal.ppat.1005545.
Murray JM, Zaunders JJ, McBride KL, Xu Y, Bailey M, Suzuki K, et al.
HIV DNA subspecies persist in both activated and resting memory CD4 T cells during antiretroviral therapy. J Virol 2014;88:3516-26. doi: 10.1128/JVI.03331-13.
Schalasta G, Börner A, Speicher A, Enders M. Comparative evaluation of the Aptima HIV-1 quant Dx assay and COBAS TaqMan HIV-1 v2.0 assay using the Roche High Pure system for the quantification of HIV-1 RNA in plasma. Clin Chem Lab Med 2016;54:493-9. doi: 10.1515/cclm-2015-0522.
Palmer S, Wiegand AP, Maldarelli F, Bazmi H, Mican JM, Polis M, et al
. New real-time reverse transcriptase-initiated PCR assay with single-copy sensitivity for human immunodeficiency virus type 1 RNA in plasma. J Clin Microbiol 2003;41:4531-6. doi: 10.1128/JCM.41.10.4531-4536.2003.
Maldarelli F, Palmer S, King MS, Wiegand A, Polis MA, Mican J, et al.
ART suppresses plasma HIV-1 RNA to a stable set point predicted by pretherapy viremia. PLoS Pathog 2007;3:e46. doi: 10.1371/journal.ppat.0030046.
Palmer S, Maldarelli F, Wiegand A, Bernstein B, Hanna GJ, Brun SC, et al.
Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. Proc Natl Acad Sci U S A 2008;105:3879-84. doi: 10.1073/pnas.0800050105.
Parisi SG, Sarmati L, Andreis S, Scaggiante R, Cruciani M, Ferretto R, et al.
Strong and persistent correlation between baseline and follow-up HIV-DNA levels and residual viremia in a population of naïve patients with more than 4 years of effective antiretroviral therapy. Clin Microbiol Infect 2015;21:288.e5-7. doi: 10.1016/j.cmi. 2014.10.009.
Chun TW, Murray D, Justement JS, Hallahan CW, Moir S, Kovacs C, et al.
Relationship between residual plasma viremia and the size of HIV proviral DNA reservoirs in infected individuals receiving effective antiretroviral therapy. J Infect Dis 2011;204:135-8. doi: 10.1093/infdis/jir208.
Martinez-Picado J, Deeks SG. Persistent HIV-1 replication during antiretroviral therapy. Curr Opin HIV AIDS 2016;11:417-23. doi: 10.1097/coh.0000000000000287.
Vancoillie L, Mortier V, Demecheleer E, Schauvliege M, Vandekerckhove L, Vogelaers D, et al.
Drug resistance is rarely the cause or consequence of long-term persistent low-level viraemia in HIV-1-infected patients on ART. Antivir Ther 2015;20:789-94. doi: 10.3851/imp2966.
Sarmati L, D′Ettorre G, Parisi SG, Andreoni M. HIV replication at low copy number and its correlation with the HIV reservoir: A clinical perspective. Curr HIV Res 2015;13:250-7. doi: 10.2174/1570162X13666150407142539.
Chun TW, Justement JS, Pandya P, Hallahan CW, McLaughlin M, Liu S, et al.
Relationship between the size of the human immunodeficiency virus type 1 (HIV-1) reservoir in peripheral blood CD4+ T cells and CD4+:CD8+ T cell ratios in aviremic HIV-1-infected individuals receiving long-term highly active antiretroviral therapy. J Infect Dis 2002;185:1672-6. doi: 10.1086/340521.
Douek DC, Brenchley JM, Betts MR, Ambrozak DR, Hill BJ, Okamoto Y, et al.
HIV preferentially infects HIV-specific CD4+ T cells. Nature 2002;417:95-8. doi: 10.1038/417095a.
Wada NI, Jacobson LP, Margolick JB, Breen EC, Macatangay B, Penugonda S, et al.
The effect of HAART-induced HIV suppression on circulating markers of inflammation and immune activation. AIDS 2015;29:463-71. doi: 10.1097/qad.0000000000000545.
Ruggiero A, De Spiegelaere W, Cozzi-Lepri A, Kiselinova M, Pollakis G, Beloukas A, et al.
During stably suppressive antiretroviral therapy integrated HIV-1 DNA load in peripheral blood is associated with the frequency of CD8 cells expressing HLA-DR/DP/DQ. EBioMedicine 2015;2:1153-9. doi: 10.1016/j.ebiom.2015.07.025.
Younas M, Psomas C, Reynes J, Corbeau P.
Immune activation in the course of HIV-1 infection: Causes, phenotypes and persistence under therapy. HIV Med 2016;17:89-105. doi: 10.1111/hiv.12310.
Hatano H, Jain V, Hunt PW, Lee TH, Sinclair E, Do TD, et al.
Cell-based measures of viral persistence are associated with immune activation and programmed cell death protein 1 (PD-1)-expressing CD4+ T cells. J Infect Dis 2013;208:50-6. doi: 10.1093/infdis/jis630.
Mavigner M, Delobel P, Cazabat M, Dubois M, L′faqihi-Olive FE, Raymond S, et al.
HIV-1 residual viremia correlates with persistent T-cell activation in poor immunological responders to combination antiretroviral therapy. LoS One 2009;4:e7658. doi: 10.1371/journal.pone.0007658.
Steel A, Cox AE, Shamji MH, John L, Nelson M, Henderson DC, et al
. HIV-1 viral replication below 50 copies/ml in patients on antiretroviral therapy is not associated with CD8+ T-cell activation. Antivir Ther 2007;12:971-5.
Buzon MJ, Martin-Gayo E, Pereyra F, Ouyang Z, Sun H, Li JZ, 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;88:10056-65. doi: 10.1128/JVI.01046-14.
Gattinoni L, Lugli E, Ji Y, Pos Z, Paulos CM, Quigley MF, et al.
A human memory T cell subset with stem cell-like properties. Nat Med 2011;17:1290-7. doi: 10.1038/nm.2446.
Farber DL, Yudanin NA, Restifo NP. Human memory T cells: Generation, compartmentalization and homeostasis. Nat Rev Immunol 2014;14:24-35. doi: 10.1038/nri3567.
Buzon MJ, Sun H, Li C, Shaw A, Seiss K, Ouyang Z, et al.
HIV-1 persistence in CD4 T cells with stem cell-like properties. Nat Med 2014;20:139-42. doi: 10.1038/nm.3445.
Jaafoura S, de Goër de Herve MG, Hernandez-Vargas EA, Hendel-Chavez H, Abdoh M, Mateo MC, et al.
Progressive contraction of the latent HIV reservoir around a core of less-differentiated CD4(+) memory T Cells. Nat Commun 2014;5:5407. doi: 10.1038/ncomms6407.
Cleret-Buhot A, Zhang Y, Planas D, Goulet JP, Monteiro P, Gosselin A, et al.
Identification of novel HIV-1 dependency factors in primary CCR4(+) CCR6(+) Th17 cells via a genome-wide transcriptional approach. Retrovirology 2015;12:102. doi: 10.1186/s12977-015-0226-9.
Sun H, Kim D, Li X, Kiselinova M, Ouyang Z, Vandekerckhove L, et al.
Th1/17 polarization of CD4 T cells supports HIV-1 persistence during antiretroviral therapy. J Virol 2015;89:11284-93. doi: 10.1128/JVI.01595-15.
Damouche A, Lazure T, Avettand-Fènoël V, Huot N, Dejucq-Rainsford N, Satie AP, et al.
Adipose tissue is a neglected viral reservoir and an inflammatory site during chronic HIV and SIV infection. PLoS Pathog 2015;11:e1005153. doi: 10.1371/journal.ppat.1005153.
Yukl SA, Sinclair E, Somsouk M, Hunt PW, Epling L, Killian M, et al.
A comparison of methods for measuring rectal HIV levels suggests that HIV DNA resides in cells other than CD4+ T cells, including myeloid cells. AIDS 2014;28:439-42. doi: 10.1097/qad. 0000000000000166.
Sheth PM, Chege D, Shin LY, Huibner S, Yue FY, Loutfy M, et al.
Immune reconstitution in the sigmoid colon after long-term HIV therapy. Mucosal Immunol 2008;1:382-8. doi: 10.1038/mi.2008.23.
Yukl SA, Shergill AK, McQuaid K, Gianella S, Lampiris H, Hare CB, et al.
Effect of raltegravir-containing intensification on HIV burden and T-cell activation in multiple gut sites of HIV-positive adults on suppressive antiretroviral therapy. AIDS 2010;24:2451-60. doi: 10.1097/QAD.0b013e32833ef7bb.
van Grevenynghe J, Cubas RA, DaFonseca S, Metcalf T, Tremblay CL, Trautmann L, et al.
Foxo3a: An integrator of immune dysfunction during HIV infection. Cytokine Growth Factor Rev 2012;23:215-21. doi: 10.1016/j.cytogfr.2012.05.008.
Sigal A, Kim JT, Balazs AB, Dekel E, Mayo A, Milo R, et al.
Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy. Nature 2011;477:95-8. doi: 10.1038/nature10347.
Klatt NR, Silvestri G. CD4+ T cells and HIV: A paradoxical Pas de Deux. Sci Transl Med 2012;4:123ps4. doi: 10.1126/scitranslmed. 3003862.
Bailey JR, Sedaghat AR, Kieffer T, Brennan T, Lee PK, Wind-Rotolo M, 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. doi: 10.1128/JVI.00591-06.
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:e1002818. doi: 10.1371/journal.ppat.1002818.