In vivo evidence for instability of episomal human immunodeficiency virus type 1 cDNA
UMass Chan Affiliations
Program in Molecular MedicineDocument Type
Journal ArticlePublication Date
2005-03-30Keywords
Acquired Immunodeficiency SyndromeAnti-HIV Agents
Base Sequence
DNA Primers
DNA, Complementary
Genomic Instability
HIV Infections
HIV-1
Humans
RNA, Viral
Reverse Transcriptase Inhibitors
Viremia
Life Sciences
Medicine and Health Sciences
Metadata
Show full item recordAbstract
Current regimens for the management of human immunodeficiency virus type 1 (HIV-1) infection suppress plasma viremia to below detectable levels for prolonged intervals. Nevertheless, there is a rapid resumption in plasma viremia if therapy is interrupted. Attempts to characterize the extent of viral replication under conditions of potent suppression and undetectable plasma viremia have been hampered by a lack of convenient assays that can distinguish latent from ongoing viral replication. Using episomal viral cDNA as a surrogate for ongoing replication, we previously presented evidence that viral replication persists in the majority of infected individuals with a sustained aviremic status. The labile nature of viral episomes and hence their validity as surrogate markers of ongoing replication in individuals with long-term-suppressed HIV-1 infection have been analyzed in short-term in vitro experiments with conflicting results. Since these in vitro experiments do not shed light on the long-term in vivo dynamics of episomal cDNA or recapitulate the natural targets of infection in vivo, we have analyzed the dynamics of episomal cDNA turnover in vivo by following the emergence of an M184V polymorphism in plasma viral RNA, in episomal cDNA, and in proviral DNA in patients on suboptimal therapies. We demonstrate that during acquisition of drug resistance, wild-type episomal cDNAs are replaced by M184V-harboring episomes. Importantly, a complete replacement of wild-type episomes with M184V-containing episomes occurred while proviruses remained wild type. This indicates that episomal cDNAs are turned over by degradation rather than through death or tissue redistribution of the infected cell itself. Therefore, evolution of episomal viral cDNAs is a valid surrogate of ongoing viral replication in HIV-1-infected individuals.Source
J Virol. 2005 Apr;79(8):5203-10. Link to article on publisher's siteDOI
10.1128/JVI.79.8.5203-5210.2005Permanent Link to this Item
http://hdl.handle.net/20.500.14038/38661PubMed ID
15795303Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1128/JVI.79.8.5203-5210.2005