PubMed ID

21383975

UMMS Affiliation

Program in Molecular Medicine

Date

2-24-2011

Document Type

Article

Subjects

Adolescent; Antiretroviral Therapy, Highly Active; DNA, Complementary; Drug Resistance, Viral; Genome, Viral; HIV Infections; HIV-1; Humans; Phylogeny; Piperazines; Pyrimidines; RNA, Viral; Receptors, CCR5; Treatment Failure; Viral Load; Viremia; Virus Replication

Disciplines

Genetics and Genomics | Immunology and Infectious Disease | Life Sciences | Medicine and Health Sciences | Microbiology

Abstract

Viral reservoirs that persist in HIV-1 infected individuals on antiretroviral therapy (ART) are the major obstacle to viral eradication. The identification and definition of viral reservoirs in patients on ART is needed in order to understand viral persistence and achieve the goal of viral eradication. We examined whether analysis of episomal HIV-1 genomes provided the means to characterize virus that persists during ART and whether it could reveal the virus that contributes to treatment failure in patients on ART. For six individuals in which virus replication was highly suppressed for at least 20 months, proviral and episomal genomes present just prior to rebound were phylogenetically compared to RNA genomes of rebounding virus after therapy interruption. Episomal envelope sequences, but not proviral envelope sequences, were highly similar to sequences in rebounding virus. Since episomes are products of recent infections, the phylogenetic relationships support the conclusion that viral rebound originated from a cryptic viral reservoir. To evaluate whether the reservoir revealed by episomal sequence analysis was of clinical relevance, we examined whether episomal sequences define a viral population that contributes to virologic failure in individuals receiving the CCR5 antagonist, Vicriviroc. Episomal envelope sequences at or near baseline predicted treatment failure due to the presence of X4 or D/M (dual/mixed) viral variants. In patients that did not harbor X4 or D/M viruses, the basis for Vicriviroc treatment failure was indeterminate. Although these samples were obtained from viremic patients, the assay would be applicable to a large percentage of aviremic patients, based on previous studies. Summarily, the results support the use of episomal HIV-1 as an additional or alternative approach to traditional assays to characterize virus that is maintained during long-term, suppressive ART.

Comments

Citation: Sharkey M, Babic DZ, Greenough T, Gulick R, Kuritzkes DR, et al. (2011) Episomal Viral cDNAs Identify a Reservoir That Fuels Viral Rebound after Treatment Interruption and That Contributes to Treatment Failure. PLoS Pathog 7(2): e1001303. doi:10.1371/journal.ppat.1001303. Link to article on publisher's site

This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.

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