Re-evaluating evolution in the HIV reservoir

Despite antiretroviral therapy (ART), a latent reservoir of replication-competent HIV-1 persists in resting memory CD4+ T-cells and precludes cure1-6. Lorenzo-Redondo et al.7 analyzed HIV-1 sequences collected from three individuals during the first six months of ART, discovered specific patterns of sequence evolution, and concluded that viral replication persists during therapy. We believe these evolutionary patterns are artifacts of rapidly decaying viral subpopulations present during the first months of therapy and are not characteristic of the long-lived reservoir. The study therefore provides no evidence that ongoing replication is an additional barrier to cure for treated individuals who consistently maintain low viral loads.

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Myeloid and CD4 T Cells Comprise the Latent Reservoir in Antiretroviral Therapy-Suppressed SIVmac251-Infected Macaques

mBio ◽

10.1128/mbio.01659-19 ◽

2019 ◽

Vol 10 (4) ◽

Cited By ~ 15

Author(s):

Celina M. Abreu ◽

Rebecca T. Veenhuis ◽

Claudia R. Avalos ◽

Shelby Graham ◽

Daymond R. Parrilla ◽

...

Keyword(s):

T Cells ◽

Antiretroviral Therapy ◽

Life Span ◽

Latent Reservoir ◽

Viral Rebound ◽

Hiv Cure ◽

Short Life ◽

Short Life Span ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Human immunodeficiency virus (HIV) eradication or long-term suppression in the absence of antiretroviral therapy (ART) requires an understanding of all viral reservoirs that could contribute to viral rebound after ART interruption. CD4 T cells (CD4s) are recognized as the predominant reservoir in HIV type 1 (HIV-1)-infected individuals. However, macrophages are also infected by HIV-1 and simian immunodeficiency virus (SIV) during acute infection and may persist throughout ART, contributing to the size of the latent reservoir. We sought to determine whether tissue macrophages contribute to the SIVmac251 reservoir in suppressed macaques. Using cell-specific quantitative viral outgrowth assays (CD4-QVOA and MΦ-QVOA), we measured functional latent reservoirs in CD4s and macrophages in ART-suppressed SIVmac251-infected macaques. Spleen, lung, and brain in all suppressed animals contained latently infected macrophages, undetectable or low-level SIV RNA, and detectable SIV DNA. Silent viral genomes with potential for reactivation and viral spread were also identified in blood monocytes, although these cells might not be considered reservoirs due to their short life span. Additionally, virus produced in the MΦ-QVOA was capable of infecting healthy activated CD4s. Our results strongly suggest that functional latent reservoirs in CD4s and macrophages can contribute to viral rebound and reestablishment of productive infection after ART interruption. These findings should be considered in the design and implementation of future HIV cure strategies. IMPORTANCE This study provides further evidence that the latent reservoir is comprised of both CD4+ T cells and myeloid cells. The data presented here suggest that CD4+ T cells and macrophages found throughout tissues in the body can contain replication-competent SIV and contribute to rebound of the virus after treatment interruption. Additionally, we have shown that monocytes in blood contain latent virus and, though not considered a reservoir themselves due to their short life span, could contribute to the size of the latent reservoir upon entering the tissue and differentiating into long-lived macrophages. These new insights into the size and location of the SIV reservoir using a model that is heavily studied in the HIV field could have great implications for HIV-infected individuals and should be taken into consideration with the development of future HIV cure strategies.

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Characterization of intact proviruses in blood and lymph node from HIV-infected individuals undergoing analytical treatment interruption

10.1101/456020 ◽

2018 ◽

Cited By ~ 2

Author(s):

Line K. Vibholm ◽

Julio C.C. Lorenzi ◽

Joy A. Pai ◽

Yehuda Z. Cohen ◽

Thiago Y. Oliveira ◽

...

Keyword(s):

T Cells ◽

Lymph Node ◽

Antiretroviral Therapy ◽

Treatment Interruption ◽

Latent Reservoir ◽

Lymphoid Tissues ◽

Analytical Treatment ◽

Hiv 1

AbstractThe role of lymphoid tissue as a potential source of HIV-1 rebound following interruption of antiretroviral therapy is uncertain. To address this issue, we compared the latent viruses obtained from CD4+ T cells in peripheral blood and lymph nodes to viruses emerging during treatment interruption. Latent viruses were characterized by sequencing near full-length (NFL) proviral DNA, and env from viral outgrowth cultures (VOAs). 5 HIV-1 infected individuals on antiretroviral therapy (ART) were studied, 4 of whom participated in a clinical trial that included an analytical treatment interruption. Intact or replication competent clonal sequences from blood and lymph node overlapped. In contrast, there was no overlap between 205 latent reservoir and 125 rebound sequences in the 4 individuals who underwent treatment interruption. However, rebound viruses could be accounted for by recombination. The data suggests that CD4+ T cells carrying latent viruses circulate between blood and lymphoid tissues in individuals on ART and support the idea that recombination may play a role in the emergence of rebound viremia.

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Models of increased latent HIV reservoir turnover prior to cART initiation imply novel clearance strategies

10.1101/2021.06.06.447292 ◽

2021 ◽

Author(s):

Aditya Jagarapu ◽

Rajveer Mann ◽

Michael J Piovoso ◽

Ryan Zurakowski

Keyword(s):

Immune Response ◽

T Cells ◽

Antiretroviral Therapy ◽

Half Life ◽

Post Treatment ◽

Latent Reservoir ◽

Treatment Control ◽

Hiv Reservoir ◽

Treatment Interruptions ◽

Exogenous Antigen

CD4+ T cells with a naive or memory phenotype carrying a replication-competent HIV provirus are recognized as the major component of the persistent HIV reservoir. These cells only mini- mally express viral protein, reducing viral cytotoxicity effects and making them difficult targets for immune responses as well as every available antiretroviral drug. In patients on suppressive antiretroviral therapy, the half-life of these cells is approximately 4-5 years, balanced by clonal expansion of the cells resulting in an overall reservoir half-life in excess of 40 years. A recent study has shown that prior to the initiation of antiretroviral therapy, the half-life of these cells is instead on the order of two weeks. We present two models explaining the wide disparity in the on- and off-treatment half-lives of the quiescent infected T cells. In the first model, generalized (antigen non-specific) immune activation due to the high HIV viral loads explains the high latent reservoir turnover rates in the absence of treatment. If this mechanism dominates, we demon- strate that reduction of the latent reservoir size is possible, either through the administration of exogenous antigen or through the use of timed treatment interruptions. In the second model, direct killing of reservoir cells by HIV drives the increased turnover off-treatment. If this mecha- nism dominates, modulation of the reservoir size is not possible by the methods described above. Previously published models of the immune response to HIV show the possibility of inducing post-treatment control by reducing the latent reservoir size; by incorporating the same immune response dynamics in our first model, it is shown that it may be possible to induce post-treatment control using either exogenous antigen administration or timed treatment interruptions.

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Induction of HIV-1 Replication in Latently Infected CD4+ T Cells Using a Combination of Cytokines

Journal of Experimental Medicine ◽

10.1084/jem.188.1.83 ◽

1998 ◽

Vol 188 (1) ◽

pp. 83-91 ◽

Cited By ~ 258

Author(s):

Tae-Wook Chun ◽

Delphine Engel ◽

Stephanie B. Mizell ◽

Linda A. Ehler ◽

Anthony S. Fauci

Keyword(s):

T Cells ◽

Antiretroviral Therapy ◽

Viral Replication ◽

Proinflammatory Cytokines ◽

Cd4 T Cells ◽

Lymphoid Tissues ◽

Tnf Α ◽

Latently Infected ◽

Hiv 1

Although it has been demonstrated that certain cytokines, particularly proinflammatory cytokines, can enhance ongoing viral replication in peripheral blood mononuclear cells (PBMCs) of HIV-1–infected individuals, it is unclear what role these cytokines play in the induction of HIV-1 replication in latently infected, resting CD4+ T cells. This study demonstrates that the in vitro combination of the proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α together with the immunoregulatory cytokine IL-2 are potent inducers of viral replication in highly purified, latently infected, resting CD4+ T cells derived from HIV-infected individuals who are antiretroviral therapy–naive as well as those who are receiving highly active antiretroviral therapy (HAART). Viral replication induced by this combination of cytokines was completely suppressed in the presence of HAART in vitro. Given that an array of cytokines, including IL-6, TNF-α, and IL-2, are copiously expressed in the microenvironment of the lymphoid tissues, which harbor the latent viral reservoirs, induction of HIV by this combination of cytokines may in part explain the commonly observed reappearance of detectable plasma viremia in HIV-infected individuals in whom HAART was discontinued. Moreover, since it is likely that these infected cells die upon activation of virus and that HAART prevents spread of virus to adjacent cells, the observation that this combination of cytokines can markedly induce viral replication in this reservoir may have important implications for the activation-mediated diminution of the latent reservoir of HIV in patients receiving HAART.

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

mBio ◽

10.1128/mbio.02121-19 ◽

2019 ◽

Vol 10 (5) ◽

Cited By ~ 6

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.

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HIV: Persistence through division

Journal of Experimental Medicine ◽

10.1084/jem.20170463 ◽

2017 ◽

Vol 214 (4) ◽

pp. 875-876 ◽

Cited By ~ 1

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.

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