scholarly journals HIV-1 Persistence in Children during Suppressive ART

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1134
Author(s):  
Mary Grace Katusiime ◽  
Gert U. Van Zyl ◽  
Mark F. Cotton ◽  
Mary F. Kearney
Keyword(s):  
Antiretroviral Therapy ◽  
Early Life ◽  
Clonal Expansion ◽  
Hiv Cure ◽  
Major Barrier ◽  
Hiv Persistence ◽  
Increased Risk ◽  
Infected Cells ◽  
Hiv 1

There is a growing number of perinatally HIV-1-infected children worldwide who must maintain life-long ART. In early life, HIV-1 infection is established in an immunologically inexperienced environment in which maternal ART and immune dynamics during pregnancy play a role in reservoir establishment. Children that initiated early antiretroviral therapy (ART) and maintained long-term suppression of viremia have smaller and less diverse HIV reservoirs than adults, although their proviral landscape during ART is reported to be similar to that of adults. The ability of these early infected cells to persist long-term through clonal expansion poses a major barrier to finding a cure. Furthermore, the effects of life-long HIV persistence and ART are yet to be understood, but growing evidence suggests that these individuals are at an increased risk for developing non-AIDS-related comorbidities, which underscores the need for an HIV cure.

scholarly journals No evidence of ongoing HIV replication or compartmentalization in tissues during combination antiretroviral therapy: Implications for HIV eradication

2019 ◽  
Vol 5 (9) ◽  
pp. eaav2045 ◽  
Author(s):  
G. Bozzi ◽  
F. R. Simonetti ◽  
S. A. Watters ◽  
E. M. Anderson ◽  
M. Gouzoulis ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Clonal Expansion ◽  
Combination Antiretroviral Therapy ◽  
Hiv Replication ◽  
Hiv Persistence ◽  
Hiv Eradication ◽  
Infected Cells ◽  
Anatomic Locations

HIV persistence during combination antiretroviral therapy (cART) is the principal obstacle to cure. Mechanisms responsible for persistence remain uncertain; infections may be maintained by persistence and clonal expansion of infected cells or by ongoing replication in anatomic locations with poor antiretroviral penetration. These mechanisms require different strategies for eradication, and determining their contributions to HIV persistence is essential. We used phylogenetic approaches to investigate, at the DNA level, HIV populations in blood, lymphoid, and other infected tissues obtained at colonoscopy or autopsy in individuals who were on cART for 8 to 16 years. We found no evidence of ongoing replication or compartmentalization of HIV; we did detect clonal expansion of infected cells that were present before cART. Long-term persistence, and not ongoing replication, is primarily responsible for maintaining HIV. HIV-infected cells present when cART is initiated represent the only identifiable source of persistence and is the appropriate focus for eradication.

scholarly journals CD161+ CD4+ T Cells Harbor Clonally Expanded Replication-Competent HIV-1 in Antiretroviral Therapy-Suppressed Individuals

mBio ◽  
2019 ◽  
Vol 10 (5) ◽  
Author(s):  
Xiaomin Li ◽  
Zhaoli Liu ◽  
Qijuan Li ◽  
Ronglin Hu ◽  
Lu Zhao ◽  
...  
Keyword(s):  
T Cells ◽  
Antiretroviral Therapy ◽  
Clonal Expansion ◽  
Latent Reservoir ◽  
Term Stability ◽  
Long Term Stability ◽  
Latently Infected ◽  
Infected Cells ◽  
Hiv 1

ABSTRACT The presence of an extremely stable latent reservoir of HIV-1 is the major obstacle to eradication, despite effective antiretroviral therapy (ART). Recent studies have shown that clonal expansion of latently infected cells without viral reactivation is an important phenomenon that maintains the long-term stability of the reservoir, yet its underlying mechanism remains unclear. Here we report that a subset of CD4+ T cells, characterized by CD161 expression on the surface, is highly permissive for HIV-1 infection. These cells possess a significantly higher survival and proliferative capacity than their CD161-negative counterparts. More importantly, we found that these cells harbor HIV-1 DNA and replication-competent latent viruses at a significantly higher frequency. By using massive single-genome proviral sequencing from ART-suppressed individuals, we confirm that CD161+ CD4+ T cells contain remarkably more identical proviral sequences, indicating clonal expansion of the viral genome in these cells. Taking the results together, our study identifies infected CD161+ CD4+ T cells to be a critical force driving the clonal expansion of the HIV-1 latent reservoir, providing a novel mechanism for the long-term stability of HIV-1 latency. IMPORTANCE The latent reservoir continues to be the major obstacle to curing HIV-1 infection. The clonal expansion of latently infected cells adds another layer maintaining the long-term stability of the reservoir, but its mechanism remains unclear. Here, we report that CD161+ CD4+ T cells serve as an important compartment of the HIV-1 latent reservoir and contain a significant amount of clonally expanded proviruses. In our study, we describe a feasible strategy that may reduce the size of the latent reservoir to a certain extent by counterbalancing the repopulation and dissemination of latently infected cells.

scholarly journals HIV: Persistence through division

2017 ◽  
Vol 214 (4) ◽  
pp. 875-876 ◽  
Author(s):  
Lillian B. Cohn ◽  
Michel C. Nussenzweig
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
T Cell Proliferation ◽  
Latent Reservoir ◽  
Major Barrier ◽  
Hiv Persistence ◽  
Hiv 1

A long-lived latent reservoir for HIV-1 persists in CD4+ T cells despite antiretroviral therapy and is the major barrier to cure. In this issue of JEM, Hosmane et al. show that T cell proliferation could explain the long-term persistence of this reservoir.

HIV Cure Strategies

2017 ◽  
Author(s):  
Boris Juelg ◽  
Rajesh Gandhi
Keyword(s):  
Gene Therapy ◽  
Antiretroviral Therapy ◽  
Immune Responses ◽  
Immune Recognition ◽  
Hiv Cure ◽  
Active Viral Replication ◽  
Infected Cells ◽  
Or Gene ◽  
Virus Expression ◽  
Hiv 1

Although current antiretroviral therapy (ART) is highly effective at controlling HIV-1 replication, it does not eradicate or cure the infection. HIV-1 persists quiescently in cellular reservoirs, not detected by the immune system due to the lack of active viral replication; these reservoirs represent the major obstacle for cure approaches. Reversal of HIV-1 latency and induction of virus expression by a variety of interventions may render infected cells susceptible to immune recognition and active clearance. Strategies to boost immune responses via vaccination, immunomodulation, or gene therapy are being evaluated with the aim of achieving HIV-1 control without antiretroviral therapy, if not viral eradication.

scholarly journals Th1/17 Polarization of CD4 T Cells Supports HIV-1 Persistence during Antiretroviral Therapy

2015 ◽  
Vol 89 (22) ◽  
pp. 11284-11293 ◽  
Author(s):  
Hong Sun ◽  
Dhohyung Kim ◽  
Xiaodong Li ◽  
Maja Kiselinova ◽  
Zhengyu Ouyang ◽  
...  
Keyword(s):  
T Cells ◽  
Antiretroviral Therapy ◽  
Cd4 T Cells ◽  
Ex Vivo ◽  
Memory Cell ◽  
Viral Reservoir ◽  
Target Cells ◽  
Infected Cells ◽  
Hiv 1

ABSTRACTThe ability to persist long term in latently infected CD4 T cells represents a characteristic feature of HIV-1 infection and the predominant barrier to efforts aiming at viral eradication and cure. Yet, increasing evidence suggests that only small subsets of CD4 T cells with specific developmental and maturational profiles are able to effectively support HIV-1 long-term persistence. Here, we analyzed how the functional polarization of CD4 T cells shapes and structures the reservoirs of HIV-1-infected cells. We found that CD4 T cells enriched for a Th1/17 polarization had elevated susceptibilities to HIV-1 infection inex vivoassays, harbored high levels of HIV-1 DNA in persons treated with antiretroviral therapy, and made a disproportionately increased contribution to the viral reservoir relative to their contribution to the CD4 T memory cell pool. Moreover, HIV-1 DNA levels in Th1/17 cells remained stable over many years of antiretroviral therapy, resulting in a progressively increasing contribution of these cells to the viral reservoir, and phylogenetic studies suggested preferential long-term persistence of identical viral sequences during prolonged antiretroviral treatment in this cell compartment. Together, these data suggest that Th1/17 CD4 T cells represent a preferred site for HIV-1 DNA long-term persistence in patients receiving antiretroviral therapy.IMPORTANCECurrent antiretroviral therapy is very effective in suppressing active HIV-1 replication but does not fully eliminate virally infected cells. The ability of HIV-1 to persist long term despite suppressive antiretroviral combination therapy represents a perplexing aspect of HIV-1 disease pathogenesis, since most HIV-1 target cells are activated, short-lived CD4 T cells. This study suggests that CD4 T helper cells with Th1/17 polarization have a preferential role as a long-term reservoir for HIV-1 infection during antiretroviral therapy, possibly because these cells may imitate some of the functional properties traditionally attributed to stem cells, such as the ability to persist for extremely long periods of time and to repopulate their own pool size through homeostatic self-renewal. These observations support the hypothesis that HIV-1 persistence is driven by small subsets of long-lasting stem cell-like CD4 T cells that may represent particularly promising targets for clinical strategies aiming at HIV-1 eradication and cure.

scholarly journals HIV Diversity and Genetic Compartmentalization in Blood and Testes during Suppressive Antiretroviral Therapy

2019 ◽  
Vol 93 (17) ◽  
Author(s):  
Rachel L. Miller ◽  
Rosalie Ponte ◽  
Bradley R. Jones ◽  
Natalie N. Kinloch ◽  
Fredrick H. Omondi ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Immune Escape ◽  
Clonal Expansion ◽  
Suppressive Therapy ◽  
Escape Mutation ◽  
Principal Mechanism ◽  
Hiv Persistence ◽  
Hiv Eradication ◽  
Infected Cells ◽  
Hiv Diversity

ABSTRACTHIV's ability to persist during suppressive antiretroviral therapy is the main barrier to cure. Immune-privileged tissues, such as the testes, may constitute distinctive sites of HIV persistence, but this has been challenging to study in humans. We analyzed the proviral burden and genetics in the blood and testes of 10 individuals on suppressive therapy who underwent elective gender-affirming surgery. HIV DNA levels in matched blood and testes were quantified by quantitative PCR, and subgenomic proviral sequences (nefregion) were characterized from single templates. HIV diversity, compartmentalization, and immune escape burden were assessed using genetic and phylogenetic approaches. Diverse proviruses were recovered from the blood (396 sequences; 354nef-intact sequences) and testes (326 sequences; 309nef-intact sequences) of all participants. Notably, the frequency of identical HIV sequences varied markedly between and within individuals. Nevertheless, proviral loads, within-host unique HIV sequence diversity, and the immune escape burden correlated positively between blood and testes. When all intactnefsequences were evaluated, 60% of participants exhibited significant blood-testis genetic compartmentalization, but none did so when the evaluation was restricted to unique sequences per site, suggesting that compartmentalization, when present, is attributable to the clonal expansion of HIV-infected cells. Our observations confirm the testes as a site of HIV persistence and suggest that individuals with larger and more diverse blood reservoirs will have larger and more diverse testis reservoirs. Furthermore, while the testis microenvironment may not be sufficiently unique to facilitate the seeding of unique viral populations therein, differential clonal expansion dynamics may be at play, which may complicate HIV eradication.IMPORTANCETwo key questions in HIV reservoir biology are whether immune-privileged tissues, such as the testes, harbor distinctive proviral populations during suppressive therapy and, if so, by what mechanism. While our results indicated that blood-testis HIV genetic compartmentalization was reasonably common (60%), it was always attributable to differential frequencies of identical HIV sequences between sites. No blood-tissue data set retained evidence of compartmentalization when only unique HIV sequences per site were considered; moreover, HIV immune escape mutation burdens were highly concordant between sites. We conclude that the principal mechanism by which blood and testis reservoirs differ is not via seeding of divergent HIV sequences therein but, rather, via differential clonal expansion of latently infected cells. Thus, while viral diversity and escape-related barriers to HIV eradication are of a broadly similar magnitude across the blood and testes, clonal expansion represents a challenge. The results support individualized analysis of within-host reservoir diversity to inform curative approaches.

scholarly journals Phenotypic analysis of the unstimulated in vivo HIV CD4 T cell reservoir

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Jason Neidleman ◽  
Xiaoyu Luo ◽  
Julie Frouard ◽  
Guorui Xie ◽  
Feng Hsiao ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Cd4 T Cell ◽  
Latent Reservoir ◽  
Hiv Cure ◽  
Phenotypic Analysis ◽  
Major Barrier ◽  
Hiv Persistence ◽  
Latently Infected ◽  
Infected Cells

The latent reservoir is a major barrier to HIV cure. As latently infected cells cannot be phenotyped directly, the features of the in vivo reservoir have remained elusive. Here, we describe a method that leverages high-dimensional phenotyping using CyTOF to trace latently infected cells reactivated ex vivo to their original pre-activation states. Our results suggest that, contrary to common assumptions, the reservoir is not randomly distributed among cell subsets, and is remarkably conserved between individuals. However, reservoir composition differs between tissues and blood, as do cells successfully reactivated by different latency reversing agents. By selecting 8–10 of our 39 original CyTOF markers, we were able to isolate highly purified populations of unstimulated in vivo latent cells. These purified populations were highly enriched for replication-competent and intact provirus, transcribed HIV, and displayed clonal expansion. The ability to isolate unstimulated latent cells from infected individuals enables previously impossible studies on HIV persistence.

scholarly journals Short Intracellular HIV-1 Transcripts as Biomarkers of Residual Immune Activation in Patients on Antiretroviral Therapy

2016 ◽  
Vol 90 (12) ◽  
pp. 5665-5676 ◽  
Author(s):  
Aya Ishizaka ◽  
Hidenori Sato ◽  
Hitomi Nakamura ◽  
Michiko Koga ◽  
Tadashi Kikuchi ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Immune Activation ◽  
Viral Suppression ◽  
Immune Status ◽  
Viral Persistence ◽  
Chronic Immune Activation ◽  
Viral Reservoirs ◽  
Increased Risk ◽  
Infected Cells ◽  
Hiv 1

ABSTRACTHIV-1 patients continue to remain at an abnormal immune status despite prolonged combination antiretroviral therapy (cART), which results in an increased risk of non-AIDS-related diseases. Given the growing recognition of the importance of understanding and controlling the residual virus in patients, additional virological markers to monitor infected cells are required. However, viral replication in circulating cells is much poorer than that in lymph nodes, which results in the absence of markers to distinguish these cells from uninfected cells in the blood. In this study, we identified prematurely terminated short HIV-1 transcripts (STs) in peripheral blood mononuclear cells (PBMCs) as an efficient intracellular biomarker to monitor viral activation and immune status in patients with cART-mediated full viral suppression in plasma. STs were detected in PBMCs obtained from both treated and untreated patients. ST levels in untreated patients generally increased with disease progression and decreased after treatment initiation. However, some patients exhibited sustained high levels of ST and low CD4+cell counts despite full viral suppression by treatment. The levels of STs strongly reflected chronic immune activation defined by coexpression of HLA-DR and CD38 on CD8+T cells, rather than circulating proviral load. These observations represent evidence for a relationship between viral persistence and host immune activation, which in turn results in the suboptimal increase in CD4+cells despite suppressive antiretroviral therapy. This cell-based measurement of viral persistence contributes to an improved understanding of the dynamics of viral persistence in cART patients and will guide therapeutic approaches targeting viral reservoirs.IMPORTANCECombination antiretroviral therapy (cART) suppresses HIV-1 load to below the detectable limit in plasma. However, the virus persists, and patients remain at an abnormal immune status, which results in an increased risk of non-AIDS-related complications. To achieve a functional cure for HIV-1 infection, activities of viral reservoirs must be quantified and monitored. However, latently infected cells are difficult to be monitored. Here, we identified prematurely terminated short HIV-1 transcripts (STs) as an efficient biomarker for monitoring viral activation and immune status in patients with cART-mediated full viral suppression in plasma. This cell-based measurement of viral persistence will contribute to our understanding of the impact of residual virus on chronic immune activation in HIV-1 patients during cART.

scholarly journals Clonal Expansion of Human Immunodeficiency Virus–Infected Cells and Human Immunodeficiency Virus Persistence During Antiretroviral Therapy

2017 ◽  
Vol 215 (suppl_3) ◽  
pp. S119-S127 ◽  
Author(s):  
James I. Mullins ◽  
Lisa M. Frenkel
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Viral Replication ◽  
Clonal Expansion ◽  
Homeostatic Proliferation ◽  
Cellular Genes ◽  
Immunodeficiency Virus ◽  
Infected Cells ◽  
Latent Hiv ◽  
Hiv 1

AbstractThe latent HIV-1 reservoir in blood decays very slowly, even during prolonged suppression of viral replication by antiretroviral therapy (ART). Mechanisms for reservoir persistence include replenishment through low-level viral replication, longevity and homeostatic proliferation of memory T cells, and most recently appreciated, clonal expansion of HIV-infected cells. Clonally expanded cells make up a large and increasing fraction of the residual infected cell population on ART, and insertion of HIV proviruses into certain host cellular genes has been associated with this proliferation. That the vast majority of proviruses are defective clouds our assessment of the degree to which clonally expanded cells harbor infectious viruses, and thus the extent to which they contribute to reservoirs relevant to curing infection. This review summarizes past studies that have defined our current understanding and the gaps in our knowledge of the mechanisms by which proviral integration and clonal expansion sustain the HIV reservoir.

scholarly journals In VitroReactivation of Replication-Competent and Infectious HIV-1 by Histone Deacetylase Inhibitors

2015 ◽  
Vol 90 (4) ◽  
pp. 1858-1871 ◽  
Author(s):  
Riddhima Banga ◽  
Francesco Andrea Procopio ◽  
Matthias Cavassini ◽  
Matthieu Perreau
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Repeated Treatment ◽  
Major Barrier ◽  
Infected Cells ◽  
Memory Cd4 T Cells ◽  
Hiv 1

ABSTRACTThe existence of long-lived HIV-1-infected resting memory CD4 T cells is thought to be the primary obstacle to HIV-1 eradication. In the search for novel therapeutic approaches that may reverse HIV-1 latency, inhibitors of histone deacetylases (HDACis) have been tested to reactivate HIV-1 replication with the objective of rendering HIV-1-infected cells susceptible to elimination either by HIV-specific CD8 T cells or through virus-mediated cytopathicity. In the present study, we evaluated the efficiency of HDACis to reactivate HIV-1 replication from resting memory CD4 T cells isolated from aviremic long-term-treated HIV-1-infected subjects. We demonstrate that following prolonged/repeated treatment of resting memory CD4 T cells with HDACis, HIV-1 replication may be induced from primary resting memory CD4 T cells isolated from aviremic long-term-treated HIV-1-infected subjects. More importantly, we demonstrate that HIV-1 reactivated in the cell cultures was not only replication competent but also infectious. Interestingly, givinostat, an HDACi that has not been investigated in clinical trials, was more efficient than vorinostat, panobinostat, and romidepsin in reversing HIV-1 latencyin vitro. Taken together, these results support further evaluation of givinostat as a latency-reversing agent (LRA) in aviremic long-term-treated HIV-1-infected subjects.IMPORTANCEThe major barrier to HIV cure is the existence of long-lived latently HIV-1-infected resting memory CD4 T cells. Latently HIV-1-infected CD4 T cells are transcriptionally silent and are therefore not targeted by conventional antiretroviral therapy (ART) or the immune system. In this context, one strategy to target latently infected cells is based on pharmacological molecules that may force the virus to replicate and would therefore render HIV-1-infected cells susceptible to elimination either by HIV-specific CD8 T cells or through virus-mediated cytopathicity. In this context, we developed an experimental strategy that would allow the evaluation of latency-reversing agent (LRA) efficiencyin vitrousing primary CD4 T cells. In the present study, we demonstrate that HDACis are potent inducers of replication-competent and infectious HIV-1 in resting memory CD4 T cells of long-term ART-treated patients and identify givinostat as the most efficient LRA tested.

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