Abstract
Mucosal mononuclear (MMC) CCR5+CD4+ T cells of the gastrointestinal (GI) tract are selectively infected and depleted during acute HIV-1 infection. Despite early initiation of combination antiretroviral therapy (cART), gut-associated lymphoid tissue (GALT) CD4+ T cell depletion and activation persist in the majority of HIV-1 positive individuals studied. This may result from ongoing HIV-1 replication and T-cell activation despite effective cART. We hypothesized that ongoing viral replication in the GI tract during cART would result in measurable viral evolution, with divergent populations emerging over time. Subjects treated during early HIV-1 infection underwent phlebotomy and flexible sigmoidoscopy with biopsies prior to and 15–24 months post initiation of cART. At the 2nd biopsy, three GALT phenotypes were noted, characterized by high, intermediate and low levels of immune activation. A representative case from each phenotype was analyzed. Each subject had plasma HIV-1 RNA levels <50 copies/ml at 2nd GI biopsy and CD4+ T cell reconstitution in the peripheral blood. Single genome amplification of full-length HIV-1 envelope was performed for each subject pre- and post-initiation of cART in GALT and PBMC. A total of 280 confirmed single genome sequences (SGS) were analyzed for experimental cases. For each subject, maximum likelihood phylogenetic trees derived from molecular sequence data showed no evidence of evolved forms in the GALT over the study period. During treatment, HIV-1 envelope diversity in GALT-derived SGS did not increase and post-treatment GALT-derived SGS showed no substantial genetic divergence from pre-treatment sequences within transmitted groups. Similar results were obtained from PBMC-derived SGS. Our results reveal that initiation of cART during acute/early HIV-1 infection can result in the interruption of measurable viral evolution in the GALT, suggesting the absence of de-novo rounds of HIV-1 replication in this compartment during suppressive cART.
Highlights
Acute infection with human immunodeficiency virus type 1 (HIV-1) is a critical time during which host factors including innate and adaptive immunity converge with virologic characteristics to determine the course of clinical progression in infected individuals [1,2,3]
Immunohistochemistry on GI biopsy specimens further demonstrated the inability of these individuals to fully reconstitute CD4+ T cells of the GI tract through specific examination of the lamina propria (LP), an important immuneeffector site where preferential CD4+ T cell depletion occurs during primary HIV infection [30]
In this study we have shown that in a group of HIV-1 infected individuals initiating therapy during early infection, no evidence of substantial viral evolution could be found in HIV-1 env variants derived from the peripheral blood mononuclear cells or gutassociated lymphoid tissue after 1–2 years of suppressive combination antiretroviral therapy (cART)
Summary
Acute infection with human immunodeficiency virus type 1 (HIV-1) is a critical time during which host factors including innate and adaptive immunity converge with virologic characteristics to determine the course of clinical progression in infected individuals [1,2,3]. Combination antiretroviral drug therapy (cART) can dramatically suppress HIV replication and reduce the plasma HIV-1 viral load in compliant patients, resulting in immune reconstitution of memory CD4+ and CD8+ T cells and the restoration of T cell immunity [8,9,10,11]. Despite these advances, current regimens remain unable to eliminate the reservoir of latent virus in resting CD4+ T lymphocytes. Cessation of therapy predictably results in the resurgence of virus replication [12,13,14,15,16,17]
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