Episomal viral cDNAs identify a reservoir that fuels viral rebound after treatment interruption and that contributes to treatment failure
UMass Chan Affiliations
Program in Molecular MedicineDocument Type
Journal ArticlePublication Date
2011-02-24Keywords
AdolescentAntiretroviral Therapy, Highly Active
DNA, Complementary
Drug Resistance, Viral
Genome, Viral
HIV Infections
HIV-1
Humans
Phylogeny
PiperazinesPyrimidinesRNA, ViralReceptors, CCR5Treatment FailureViral LoadViremiaVirus ReplicationGenetics and GenomicsImmunology and Infectious DiseaseLife SciencesMedicine and Health SciencesMicrobiology
Metadata
Show full item recordAbstract
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.Source
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 siteDOI
10.1371/journal.ppat.1001303Permanent Link to this Item
http://hdl.handle.net/20.500.14038/39553PubMed ID
21383975Related Resources
Link to Article in PubMedRights
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