Variable contexts and levels of hypermutation in HIV-1 proviral genomes recovered from primary peripheral blood mononuclear cells.
APOBEC-mediated cytidine deamination of HIV-1 genomes during reverse transcription has been shown to be a potent mechanism of host restriction for HIV-1 infection ex vivo and in vitro. However, this defense system can be overcome by the viral protein Vif. Unlike other mechanisms of host restriction, the APOCEC-Vif interaction leaves an imprint on integrated proviruses in the form of G-->A hypermutation. In the current work we systematically studied levels, contexts, and patterns of HIV-1 hypermutation in vivo. The analysis of 24 full-genome HIV-1 sequences retrieved from primary PBMCs, representing infections with several HIV-1 clades, and the inclusion of 7 cognate pairs of hypermutated/non-hypermutated sequences derived from the same patient sample, provided a comprehensive view of the characteristics of APOBEC-mediated restriction in vivo. Levels of hypermutation varied nearly 5-fold among the studied proviruses. GpG motifs were most frequently affected (22/24 proviruses). Levels of hypermutation varied across the genome. The reported "twin peak" pattern of hypermutation was observed in 18/24 hypermutants, but the remainder exhibited singular non-conforming patterns. These data suggest considerable complexity in the interplay of host restriction and viral defense during HIV-1 infection.
Kijak
Gustavo H
GH
Henry M. Jackson Foundation for the Advancement of Military Medicine/US Military HIV Research Program, 1600 East Gude Drive, Rockville, Maryland 20850, USA. gkijak@hivresearch.org
Janini
Luiz Mario
LM
Tovanabutra
Sodsai
S
Sanders-Buell
Eric
E
Arroyo
Miguel Angel
MA
Robb
Merlin L
ML
Michael
Nelson L
NL
Birx
Debora L
DL
McCutchan
Francine E
FE
D001769:Blood / Q000821:virology*; D016679:Genome, Viral; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology*; D008969:Molecular Sequence Data; D009154:Mutation; D011533:Proviruses / Q000235:genetics*; D017422:Sequence Analysis, DNA