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- Title
Quantitative deep sequencing reveals dynamic HIV-1 escape and large population shifts during CCR5 antagonist therapy in vivo.
- Authors
Tsibris, Athe M N; Korber, Bette; Arnaout, Ramy; Russ, Carsten; Lo, Chien-Chi; Leitner, Thomas; Gaschen, Brian; Theiler, James; Paredes, Roger; Su, Zhaohui; Hughes, Michael D; Gulick, Roy M; Greaves, Wayne; Coakley, Eoin; Flexner, Charles; Nusbaum, Chad; Kuritzkes, Daniel R
- Abstract
High-throughput sequencing platforms provide an approach for detecting rare HIV-1 variants and documenting more fully quasispecies diversity. We applied this technology to the V3 loop-coding region of env in samples collected from 4 chronically HIV-infected subjects in whom CCR5 antagonist (vicriviroc [VVC]) therapy failed. Between 25,000-140,000 amplified sequences were obtained per sample. Profound baseline V3 loop sequence heterogeneity existed; predicted CXCR4-using populations were identified in a largely CCR5-using population. The V3 loop forms associated with subsequent virologic failure, either through CXCR4 use or the emergence of high-level VVC resistance, were present as minor variants at 0.8-2.8% of baseline samples. Extreme, rapid shifts in population frequencies toward these forms occurred, and deep sequencing provided a detailed view of the rapid evolutionary impact of VVC selection. Greater V3 diversity was observed post-selection. This previously unreported degree of V3 loop sequence diversity has implications for viral pathogenesis, vaccine design, and the optimal use of HIV-1 CCR5 antagonists.
- Publication
PloS one, 2009, Vol 4, Issue 5, pe5683
- ISSN
1932-6203
- Publication type
Journal Article
- DOI
10.1371/journal.pone.0005683