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The HIV-1 reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time.

ABSTRACT: The source and dynamics of persistent HIV-1 during long-term combinational antiretroviral therapy (cART) are critical to understanding the barriers to curing HIV-1 infection. To address this issue, we isolated and genetically characterized HIV-1 DNA from naïve and memory T cells from peripheral blood and gut-associated lymphoid tissue (GALT) from eight patients after 4-12 y of suppressive cART. Our detailed analysis of these eight patients indicates that persistent HIV-1 in peripheral blood and GALT is found primarily in memory CD4(+) T cells [CD45RO(+)/CD27((+/-))]. The HIV-1 infection frequency of CD4(+) T cells from peripheral blood and GALT was higher in patients who initiated treatment during chronic compared with acute/early infection, indicating that early initiation of therapy results in lower HIV-1 reservoir size in blood and gut. Phylogenetic analysis revealed an HIV-1 genetic change between RNA sequences isolated before initiation of cART and intracellular HIV-1 sequences from the T-cell subsets after 4-12 y of suppressive cART in four of the eight patients. However, evolutionary rate analyses estimated no greater than three nucleotide substitutions per gene region analyzed during all of the 4-12 y of suppressive therapy. We also identified a clearly replication-incompetent viral sequence in multiple memory T cells in one patient, strongly supporting asynchronous cell replication of a cell containing integrated HIV-1 DNA as the source. This study indicates that persistence of a remarkably stable population of infected memory cells will be the primary barrier to a cure, and, with little evidence of viral replication, this population could be maintained by homeostatic cell proliferation or other processes.

SUBMITTER: Josefsson L

PROVIDER: S-EPMC3870728 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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The HIV-1 reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time.

Josefsson Lina L von Stockenstrom Susanne S Faria Nuno R NR Sinclair Elizabeth E Bacchetti Peter P Killian Maudi M Epling Lorrie L Tan Alice A Ho Terence T Lemey Philippe P Shao Wei W Hunt Peter W PW Somsouk Ma M Wylie Will W Douek Daniel C DC Loeb Lisa L Custer Jeff J Hoh Rebecca R Poole Lauren L Deeks Steven G SG Hecht Frederick F Palmer Sarah S

Proceedings of the National Academy of Sciences of the United States of America 20131125 51

The source and dynamics of persistent HIV-1 during long-term combinational antiretroviral therapy (cART) are critical to understanding the barriers to curing HIV-1 infection. To address this issue, we isolated and genetically characterized HIV-1 DNA from naïve and memory T cells from peripheral blood and gut-associated lymphoid tissue (GALT) from eight patients after 4-12 y of suppressive cART. Our detailed analysis of these eight patients indicates that persistent HIV-1 in peripheral blood and ...[more]

PMID: 24277811

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Project description:Introduction:Human immunodeficiency virus (HIV) infection results in a gradual depletion of immune function, particularly CD4 cells. The CD4 assessment plays a significant role in assessing treatment responses and clinical decision-making for patients on combination antiretroviral therapy (ART) in resource-limited settings. However, new data on CD4 count changes are scarce; the volatility of CD4 counts after initiation of ART over time remains largely uncharacterized. This study aimed to identify the predictors of CD4 changes over time among HIV-infected children who began ART in Amhara, Ethiopia. Methods:A retrospective follow-up study was performed. A total of 983 HIV-infected children who initiated ART in government hospitals in the Amhara region between 2010 and 2016 were included using a simple random sampling technique. Data were extracted using a structured checklist. An exploratory data analysis was carried out to explain individual and average profile plots. The linear mixed model was used to identify the CD4 change count predictors over time. Variables with p value < 0.05 were considered statistically significant in a multivariable linear mixed regression analysis. Results:The mean CD4 count of the participants was 465.1 cells/mm3 with an average CD4 count increase of 30.06 cells/mm3 over 6 months from baseline CD4 count and ART initiation. Childhood age (? = - 0.015; 95% Cl - 0.021, - 0.009), opportunistic infection at ART initiation (? = - 0.044, 95% CI - 0.085, - 0.004), hemoglobin level (? = 0.013; 95% CI 0.004, 0.022), and baseline WHO clinical stage II (? = - 0.046, 95% CI - 0.091, - 0.0003) were significant predictors of CD4 changes over time. Conclusions:The average CD4 count increase was sufficient in HIV patients who began combined antiretroviral therapy over time. The younger age of the infant, the higher baseline level of hemoglobin, the baseline WHO clinical stage II, and opportunistic infections led to changes in CD4 counts. As a result, timely diagnosis and treatment of opportunistic infections will reduce the risk of opportunistic infections.

Project description:Monitoring the efficacy of novel reservoir-reducing treatments for HIV is challenging. The limited ability to sample and quantify latent infection means that supervised antiretroviral therapy (ART) interruption studies are generally required. Here we introduce a set of mathematical and statistical modeling tools to aid in the design and interpretation of ART-interruption trials. We show how the likely size of the remaining reservoir can be updated in real-time as patients continue off treatment, by combining the output of laboratory assays with insights from models of reservoir dynamics and rebound. We design an optimal schedule for viral load sampling during interruption, whereby the frequency of follow-up can be decreased as patients continue off ART without rebound. While this scheme can minimize costs when the chance of rebound between visits is low, we find that the reservoir will be almost completely reseeded before rebound is detected unless sampling occurs at least every two weeks and the most sensitive viral load assays are used. We use simulated data to predict the clinical trial size needed to estimate treatment effects in the face of highly variable patient outcomes and imperfect reservoir assays. Our findings suggest that large numbers of patients-between 40 and 150-will be necessary to reliably estimate the reservoir-reducing potential of a new therapy and to compare this across interventions. As an example, we apply these methods to the two "Boston patients", recipients of allogeneic hematopoietic stem cell transplants who experienced large reductions in latent infection and underwent ART-interruption. We argue that the timing of viral rebound was not particularly surprising given the information available before treatment cessation. Additionally, we show how other clinical data can be used to estimate the relative contribution that remaining HIV+ cells in the recipient versus newly infected cells from the donor made to the residual reservoir that eventually caused rebound. Together, these tools will aid HIV researchers in the evaluating new potentially-curative strategies that target the latent reservoir.

Dataset Information

The HIV-1 reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time.

Publications

The HIV-1 reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time.

Similar Datasets

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