scholarly journals Kinetics of Plasma HIV Rebound in the Era of Modern Antiretroviral Therapy

2020 ◽  
Vol 222 (10) ◽  
pp. 1655-1659 ◽  
Author(s):  
Michael C Sneller ◽  
Erin D Huiting ◽  
Katherine E Clarridge ◽  
Catherine Seamon ◽  
Jana Blazkova ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Antiretroviral Therapy ◽  
Therapeutic Efficacy ◽  
Historical Data ◽  
Modern Art ◽  
Treatment Interruption ◽  
Viral Rebound ◽  
Hiv Cure ◽  
Analytical Treatment ◽  
Kinetics Of

Abstract Historical data regarding time to viral rebound following analytical treatment interruption (ATI) have been used to determine therapeutic efficacy in HIV cure trials; however, such data were collected from studies conducted a decade or more ago and included participants receiving older antiretroviral therapy (ART) regimens with infrequent virologic monitoring. We conducted a study of 22 HIV-infected participants receiving modern ART to determine the kinetics of plasma viral rebound following ATI. Our data suggest that modern ART does not alter kinetics of viral rebound when compared to previous regimens and that immunologic interventions may be necessary to achieve ART-free virologic remission. Clinical Trials Registration ClinicaTrials.gov identifier: NCT03225118.

scholarly journals Infectious Virus Persists in CD4+T Cells and Macrophages in Antiretroviral Therapy-Suppressed Simian Immunodeficiency Virus-Infected Macaques

2019 ◽  
Vol 93 (15) ◽  
Author(s):  
Celina M. Abreu ◽  
Rebecca T. Veenhuis ◽  
Claudia R. Avalos ◽  
Shelby Graham ◽  
Suzanne E. Queen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Infectious Virus ◽  
Treatment Interruption ◽  
Viral Rebound ◽  
Hiv Cure ◽  
Macaque Model ◽  
Immunodeficiency Virus ◽  
Latently Infected

ABSTRACTUnderstanding the cellular and anatomical sites of latent virus that contribute to human immunodeficiency virus (HIV) rebound is essential for eradication. In HIV-positive patients, CD4+T lymphocytes comprise a well-defined functional latent reservoir, defined as cells containing transcriptionally silent genomes able to produce infectious virus once reactivated. However, the persistence of infectious latent virus in CD4+T cells in compartments other than blood and lymph nodes is unclear. Macrophages (Mϕ) are infected by HIV/simian immunodeficiency virus (SIV) and are likely to carry latent viral genomes during antiretroviral therapy (ART), contributing to the reservoir. Currently, the gold standard assay used to measure reservoirs containing replication-competent virus is the quantitative viral outgrowth assay (QVOA). Using an SIV-macaque model, the CD4+T cell and Mϕ functional latent reservoirs were measured in various tissues using cell-specific QVOAs. Our results showed that blood, spleen, and lung in the majority of suppressed animals contain latently infected Mϕs. Surprisingly, the numbers of CD4+T cells, monocytes, and Mϕs carrying infectious genomes in blood and spleen were at comparable frequencies (∼1 infected cell per million). We also demonstrate thatex vivoviruses produced in the Mϕ QVOA are capable of infecting activated CD4+T cells. These results strongly suggest that latently infected tissue Mϕs can reestablish productive infection upon treatment interruption. This study provides the first comparison of CD4+T cell and Mϕ functional reservoirs in a macaque model. It is the first confirmation of the persistence of latent genomes in monocytes in blood and Mϕs in the spleen and lung of SIV-infected ART-suppressed macaques. Our results demonstrate that transcriptionally silent genomes in Mϕs can contribute to viral rebound after ART interruption and should be considered in future HIV cure strategies.IMPORTANCEThis study suggests that CD4+T cells found throughout tissues in the body can contain replication-competent SIV and contribute to rebound of the virus after treatment interruption. In addition, this study demonstrates that macrophages in tissues are another cellular reservoir for SIV and may contribute to viral rebound after treatment interruption. This new insight into the size and location of the SIV reservoir could have great implications for HIV-infected individuals and should be taken into consideration for the development of future HIV cure strategies.

scholarly journals Anti-HIV-1 ADCC Antibodies following Latency Reversal and Treatment Interruption

2017 ◽  
Vol 91 (15) ◽  
Author(s):  
Wen Shi Lee ◽  
Anne B. Kristensen ◽  
Thomas A. Rasmussen ◽  
Martin Tolstrup ◽  
Lars Østergaard ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Treatment Interruption ◽  
Viral Rebound ◽  
Analytical Treatment ◽  
Antigenic Stimulus ◽  
Latently Infected ◽  
Infected Cells ◽  
Functional Antibodies ◽  
Hiv 1 ◽  
Reversing Agents

ABSTRACT There is growing interest in utilizing antibody-dependent cellular cytotoxicity (ADCC) to eliminate infected cells following reactivation from HIV-1 latency. A potential barrier is that HIV-1-specific ADCC antibodies decline in patients on long-term antiretroviral therapy (ART) and may not be sufficient to eliminate reactivated latently infected cells. It is not known whether reactivation from latency with latency-reversing agents (LRAs) could provide sufficient antigenic stimulus to boost HIV-1-specific ADCC. We found that treatment with the LRA panobinostat or a short analytical treatment interruption (ATI), 21 to 59 days, was not sufficient to stimulate an increase in ADCC-competent antibodies, despite viral rebound in all subjects who underwent the short ATI. In contrast, a longer ATI, 2 to 12 months, among subjects enrolled in the Strategies for Management of Antiretroviral Therapy (SMART) trial robustly boosted HIV-1 gp120-specific Fc receptor-binding antibodies and ADCC against HIV-1-infected cells in vitro. These results show that there is a lag between viral recrudescence and the boosting of ADCC antibodies, which has implications for strategies toward eliminating latently infected cells. IMPORTANCE The “shock and kill” HIV-1 cure strategy aims to reactivate HIV-1 expression in latently infected cells and subsequently eliminate the reactivated cells through immune-mediated killing. Several latency reversing agents (LRAs) have been examined in vivo, but LRAs alone have not been able to achieve HIV-1 remission and prevent viral rebound following analytical treatment interruption (ATI). In this study, we examined whether LRA treatment or ATI can provide sufficient antigenic stimulus to boost HIV-1-specific functional antibodies that can eliminate HIV-1-infected cells. Our study has implications for the antigenic stimulus required for antilatency strategies and/or therapeutic vaccines to boost functional antibodies and assist in eliminating the latent reservoir.

scholarly journals Preexposure Prophylaxis for Mitigating Risk of HIV Transmission During HIV Cure–Related Clinical Trials With a Treatment Interruption

2019 ◽  
Vol 220 (Supplement_1) ◽  
pp. S16-S18 ◽  
Author(s):  
Jean-Daniel Lelièvre
Keyword(s):  
Human Immunodeficiency Virus ◽  
Clinical Trials ◽  
Hiv Transmission ◽  
Treatment Interruption ◽  
Sex Partners ◽  
Hiv Cure ◽  
Analytical Treatment ◽  
Secondary Transmission ◽  
Preexposure Prophylaxis ◽  
Immunodeficiency Virus

AbstractAnalytical treatment interruption performed during human immunodeficiency virus (HIV) cure–related clinical trials exposes sex partners of participants in these trials to a risk of HIV transmission. Preexposure prophylaxis (PrEP), which emerged in recent years as a key strategy for preventing HIV transmission, is often considered a useful tool to prevent this risk. This article supports offering PrEP to the stable sex partners of participants in these trials but also notes limitations that must be addressed. It concludes that PrEP cannot on its own eliminate the risk of secondary transmission in this context.

scholarly journals Origin of Rebound Plasma HIV Includes Cells with Identical Proviruses That Are Transcriptionally Active before Stopping of Antiretroviral Therapy

2015 ◽  
Vol 90 (3) ◽  
pp. 1369-1376 ◽  
Author(s):  
Mary F. Kearney ◽  
Ann Wiegand ◽  
Wei Shao ◽  
John M. Coffin ◽  
John W. Mellors ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Antiretroviral Therapy ◽  
Opportunistic Infections ◽  
Treatment Interruption ◽  
Viral Rebound ◽  
Proliferating Cells ◽  
Peripheral Blood Mononuclear ◽  
Hiv Reservoir ◽  
Infected Cells ◽  
Aids Clinical Trials

ABSTRACTUnderstanding the origin of HIV variants during viral rebound may provide insight into the composition of the HIV reservoir and has implications for the design of curative interventions. HIV single-genome sequences were obtained from 10 AIDS Clinical Trials Group participants who underwent analytic antiretroviral therapy (ART) interruption (ATI). Rebounding variants were compared with those in pre-ART plasma in all 10 participants and with on-ART peripheral blood mononuclear cell (PBMC)-associated DNA and RNA (CA-RNA) in 7/10 participants. The highest viral diversities were found in the DNA and CA-RNA populations. In 3 of 7 participants, we detected multiple, identical DNA and CA-RNA sequences during suppression on ART that exactly matched plasma HIV sequences. Hypermutated DNA and CA-RNA were detected in four participants, contributing to diversities in these compartments that were higher than in the pre-ART and post-ATI plasma. Shifts in the viral rebound populations could be detected in some participants over the 2- to 3-month observation period. These findings suggest that a source of initial rebound viremia could be populations of infected cells that clonally expanded prior to and/or during ART, some of which were already expressing HIV RNA before treatment was interrupted. These clonally expanding populations of HIV-infected cells may represent an important target for strategies aimed at achieving reservoir reduction and sustained virologic remission.IMPORTANCEAntiretroviral therapy alone cannot eradicate the HIV reservoir, and viral rebound is generally rapid after treatment interruption. It has been suggested that clonal expansion of HIV-infected cells is an important mechanism of HIV reservoir persistence, but the contribution of these clonally proliferating cells to the rebounding virus is unknown. We report a study of AIDS Clinical Trials Group participants who underwent treatment interruption and compared rebounding plasma virus with that found within cells prior to treatment interruption. We found several incidences in which plasma HIV variants exactly matched that of multiple proviral DNA copies from infected blood cells sampled before treatment interruption. In addition, we found that these cells were not dormant but were generating unspliced RNA transcripts before treatment was interrupted. Identification of the HIV reservoir and determining its mechanisms for persistence may aid in the development of strategies toward a cure for HIV. (This study was presented in part at the Conference on Retroviruses and Opportunistic Infections, Seattle, WA, February 23 to 26 2015.)

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

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
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.

scholarly journals Effect of analytical treatment interruption and reinitiation of antiretroviral therapy on HIV reservoirs and immunologic parameters in infected individuals

2018 ◽  
Vol 14 (1) ◽  
pp. e1006792 ◽  
Author(s):  
Katherine E. Clarridge ◽  
Jana Blazkova ◽  
Kevin Einkauf ◽  
Mary Petrone ◽  
Eric W. Refsland ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Treatment Interruption ◽  
Analytical Treatment ◽  
Hiv Reservoirs ◽  
Immunologic Parameters

scholarly journals Characterization of Intact Proviruses in Blood and Lymph Node from HIV-Infected Individuals Undergoing Analytical Treatment Interruption

2019 ◽  
Vol 93 (8) ◽  
Author(s):  
Line K. Vibholm ◽  
Julio C. C. Lorenzi ◽  
Joy A. Pai ◽  
Yehuda Z. Cohen ◽  
Thiago Y. Oliveira ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
Treatment Interruption ◽  
Latent Reservoir ◽  
Lymphoid Tissues ◽  
Viral Rebound ◽  
Analytical Treatment ◽  
Latent Hiv ◽  
Hiv 1

ABSTRACT The role of lymphoid tissue as a potential source of HIV-1 rebound following interruption of antiretroviral therapy (ART) 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 assays (VOAs). Five HIV-1-infected individuals on ART were studied, four of whom participated in a clinical trial of a TLR9 agonist that included an analytical treatment interruption. We found that 98% of intact or replication-competent clonal sequences overlapped between blood and lymph node. In contrast, there was no overlap between 205 latent reservoir and 125 rebound sequences in the four individuals who underwent treatment interruption. However, rebound viruses could be accounted for by recombination. The data suggest 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. IMPORTANCE HIV-1 persists as a latent infection in CD4+ T cells that can be found in lymphoid tissues in infected individuals during ART. However, the importance of this tissue reservoir and its contribution to viral rebound upon ART interruption are not clear. In this study, we sought to compare latent HIV-1 from blood and lymph node CD4+ T cells from five HIV-1-infected individuals. Further, we analyzed the contribution of lymph node viruses to viral rebound. We observed that the frequencies of intact proviruses were the same in blood and lymph node. Moreover, expanded clones of T cells bearing identical proviruses were found in blood and lymph node. These latent reservoir sequences did not appear to be the direct origin of rebound virus. Instead, latent proviruses were found to contribute to the rebound compartment by recombination.

scholarly journals Impact of Treatment Interruption on HIV Reservoirs and Lymphocyte Subsets in Individuals Who Initiated Antiretroviral Therapy During the Early Phase of Infection

2019 ◽  
Vol 220 (2) ◽  
pp. 270-274 ◽  
Author(s):  
Erin D Huiting ◽  
Kathleen Gittens ◽  
J Shawn Justement ◽  
Victoria Shi ◽  
Jana Blazkova ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Early Phase ◽  
Lymphocyte Subsets ◽  
Treatment Interruption ◽  
Therapeutic Strategies ◽  
Clinical Protocols ◽  
Analytical Treatment ◽  
Hiv Reservoirs ◽  
Immunodeficiency Virus

Abstract Therapeutic strategies for achieving sustained virologic remission are being explored in human immunodeficiency virus (HIV)–infected individuals who began antiretroviral therapy (ART) during the early phase of infection. In the evaluation of such therapies, clinical protocols should include analytical treatment interruption (ATI); however, the immunologic and virologic impact of ATI in individuals who initiated ART early has not been fully delineated. We demonstrate that ATI causes neither expansion of HIV reservoirs nor immunologic abnormalities following reinitiation of ART. Our findings support the use of ATI to determine whether sustained virologic remission has been achieved in clinical trials of individuals who initiated ART early during HIV infection.

scholarly journals Acceptability, motivation and the prospect of cure for people living with HIV and their healthcare providers in HIV cure-focused treatment interruption studies

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Jillian S. Y. Lau ◽  
Miranda Z. Smith ◽  
Brent Allan ◽  
Cipriano Martinez ◽  
Jennifer Power ◽  
...  
Keyword(s):  
Descriptive Analysis ◽  
Healthcare Providers ◽  
Treatment Interruption ◽  
People Living With Hiv ◽  
Hiv Cure ◽  
Educational Strategies ◽  
Analytical Treatment ◽  
Clinical Endpoints ◽  
Treatment Interruptions ◽  
Living With Hiv

Abstract Background Analytical treatment interruptions (ATI) are commonly used clinical endpoints to assess interventions aimed at curing HIV or achieving antiretroviral therapy (ART)-free HIV remission. Understanding the acceptability of ATI amongst people living with HIV (PLHIV) and their HIV healthcare providers (HHP) is limited. Methods Two online surveys for PLHIV and HHP assessed awareness and acceptability of ATI, and understanding of the prospect for HIV cure in the future. Responses were collected from July 2017–January 2018. A descriptive analysis was performed and similar questions across the two surveys were compared using χ squared test. Results 442 PLHIV and 144 HHP completed the survey. 105/400 (26%) PLHIV had ever interrupted ART, 8% of which were in a clinical trial. Altruistic motivations were drivers of participation of PLHIV in cure related research. 81/135 (60%) HHP would support their patients wishing to enrol in an HIV cure-focused trial, but fewer would promote and allow such participation (25% and 31% respectively). Compared to HHP, PLHIV were more likely to believe that an HIV cure would be achievable within 10 years (55% vs. 19%, p < 0.001), had less awareness of ATI (46% vs. 62%, p < 0.001) and were less likely to have had experience of either participation or enrolment in an ATI study (5% vs. 18%, p < 0.001) Conclusion PLHIV were more optimistic about the potential for HIV cure. HHP had more direct experience with HIV cure-focused studies. Educational strategies are required for both groups to increase understanding around ATIs in HIV cure research but should be tailored specifically to each group.

scholarly journals Antibody Responses After Analytic Treatment Interruption in Human Immunodeficiency Virus-1-Infected Individuals on Early Initiated Antiretroviral Therapy

2016 ◽  
Vol 3 (2) ◽  
Author(s):  
Kathryn E. Stephenson ◽  
George H. Neubauer ◽  
Christine A. Bricault ◽  
Jennifer Shields ◽  
Madeleine Bayne ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Treatment Interruption ◽  
Antibody Responses ◽  
Viral Rebound ◽  
Analytic Treatment ◽  
Antibody Maturation ◽  
Neutralizing Capacity ◽  
Immunodeficiency Virus ◽  
Hiv 1

Abstract The examination of antibody responses in human immunodeficiency virus (HIV)-1-infected individuals in the setting of antiretroviral treatment (ART) interruption can provide insight into the evolution of antibody responses during viral rebound. In this study, we assessed antibody responses in 20 subjects in AIDS Clinical Trials Group A5187, wherein subjects were treated with antiretroviral therapy during acute/early HIV-1 infection, underwent analytic treatment interruption, and subsequently demonstrated viral rebound. Our data suggest that early initiation of ART arrests the maturation of HIV-1-specific antibody responses, preventing epitope diversification of antibody binding and the development of functional neutralizing capacity. Antibody responses do not appear permanently blunted, however, because viral rebound triggered the resumption of antibody maturation in our study. We also found that antibody responses measured by these assays did not predict imminent viral rebound. These data have important implications for the HIV-1 vaccine and eradication fields.

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