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Recovery of replication-competent residual HIV-1 from plasma of a patient receiving prolonged, suppressive highly active antiretroviral therapy.

ABSTRACT: The clinical significance of persistent residual viremia in patients on prolonged highly active antiretroviral therapy (HAART) is not clear. Moreover, it remains to be demonstrated whether residual viremia consists of viruses capable of spreading infection in vivo upon termination of therapy. Using residual viral RNAs (vRNAs) isolated from a HAART-treated patient's plasma, we cloned full-length viral genomes and found that most of them could produce infectious, replication-competent HIVs when transfected into TZM-bl cells, suggesting that residual viruses produced in the absence of therapy can initiate fresh cycles of infection and spread in host cells. The data further indicate that residual viremia may pose a major concern with regard to the emergence of drug-resistant HIVs during periods of low adherence to therapy.

SUBMITTER: Sahu GK

PROVIDER: S-EPMC2916539 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Recovery of replication-competent residual HIV-1 from plasma of a patient receiving prolonged, suppressive highly active antiretroviral therapy.

Sahu Gautam K GK Sarria Juan C JC Cloyd Miles W MW

Journal of virology 20100602 16

The clinical significance of persistent residual viremia in patients on prolonged highly active antiretroviral therapy (HAART) is not clear. Moreover, it remains to be demonstrated whether residual viremia consists of viruses capable of spreading infection in vivo upon termination of therapy. Using residual viral RNAs (vRNAs) isolated from a HAART-treated patient's plasma, we cloned full-length viral genomes and found that most of them could produce infectious, replication-competent HIVs when tr ...[more]

PMID: 20519388

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Project description:Viruses that persist despite seemingly effective antiretroviral treatment (ART) and can reinitiate infection if treatment is stopped preclude definitive treatment of HIV-1 infected individuals, requiring lifelong ART. Among strategies proposed for targeting these viral reservoirs, the premise of the "shock and kill" strategy is to induce expression of latent proviruses [for example with histone deacetylase inhibitors (HDACis)] resulting in elimination of the affected cells through viral cytolysis or immune clearance mechanisms. Yet, ex vivo studies reported that HDACis have variable efficacy for reactivating latent proviruses, and hinder immune functions. We developed a nonhuman primate model of post-treatment control of SIV through early and prolonged administration of ART and performed in vivo reactivation experiments in controller RMs, evaluating the ability of the HDACi romidepsin (RMD) to reactivate SIV and the impact of RMD treatment on SIV-specific T cell responses. Ten RMs were IV-infected with a SIVsmmFTq transmitted-founder infectious molecular clone. Four RMs received conventional ART for >9 months, starting from 65 days post-infection. SIVsmmFTq plasma viremia was robustly controlled to <10 SIV RNA copies/mL with ART, without viral blips. At ART cessation, initial rebound viremia to ~106 copies/mL was followed by a decline to < 10 copies/mL, suggesting effective immune control. Three post-treatment controller RMs received three doses of RMD every 35-50 days, followed by in vivo experimental depletion of CD8+ cells using monoclonal antibody M-T807R1. RMD was well-tolerated and resulted in a rapid and massive surge in T cell activation, as well as significant virus rebounds (~104 copies/ml) peaking at 5-12 days post-treatment. CD8+ cell depletion resulted in a more robust viral rebound (107 copies/ml) that was controlled upon CD8+ T cell recovery. Our results show that RMD can reactivate SIV in vivo in the setting of post-ART viral control. Comparison of the patterns of virus rebound after RMD administration and CD8+ cell depletion suggested that RMD impact on T cells is only transient and does not irreversibly alter the ability of SIV-specific T cells to control the reactivated virus.

Project description:BackgroundMinimizing antiretroviral treatment failure is crucial for improving patient health and for maintaining long-term access to care in low-income settings such as eastern Africa. To develop interventions to support adherence, policymakers must understand the extent and scope of treatment failure in their programs. However, estimates of treatment failure in eastern Africa have been variable and inconclusive.ObjectiveThis systematic review and meta-analysis sought to determine the pooled prevalence of immunological failure among adults receiving antiretroviral therapy in eastern Africa.MethodsWe performed a systematic search of the PubMed, Google Scholar, Excerpta Medica Database, and the World Health Organization's Hinari portal (which includes the Scopus, African Index Medicus, and African Journals Online databases) databases. Unpublished studies were also accessed from conference websites and university repositories. We used Stata version 14 for data analysis. The Cochrane Q test and I 2 test statistic were used to test for heterogeneity across the studies. Due to high levels of heterogeneity, a random effects model was used to estimate the pooled prevalence of immunological failure. Begg and Egger tests of the intercept in the random effects model were used to check for publication bias.ResultsAfter removing duplicates, 25 articles remained for assessment and screening. After quality screening, 15 articles were deemed eligible and incorporated into the final analysis. The average pooled estimate of immunological treatment failure prevalence was found to be 21.89% (95% CI, 15.14-28.64). In the subgroup analysis conducted by geographic region, the pooled prevalence of immunological treatment failure in Ethiopia was 15.2% (95% CI, 12.27-18.13) while in Tanzania it was 53.93% (95% CI, 48.14-59.73). Neither the results of Egger test or Begg tests suggested publication bias; however, on visual examination, the funnel plot appeared asymmetric. The large heterogeneity across the studies could be explained by study country.ConclusionImmunological treatment failure among patients receiving antiretroviral therapy in eastern Africa was high, and greater than previously reported. The relatively low rates of treatment failure found in Ethiopia suggest that its health extension program should be studied as a model for improving adherence in the region. (Curr Ther Res Clin Exp. 2021; 82:XXX-XXX) © 2021 Elsevier HS Journals, Inc.

Dataset Information

Recovery of replication-competent residual HIV-1 from plasma of a patient receiving prolonged, suppressive highly active antiretroviral therapy.

Publications

Recovery of replication-competent residual HIV-1 from plasma of a patient receiving prolonged, suppressive highly active antiretroviral therapy.

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