Quantitative deep sequencing reveals dynamic HIV-1 escape and large population shifts during CCR5 antagonist therapy in vivo.

TitleQuantitative deep sequencing reveals dynamic HIV-1 escape and large population shifts during CCR5 antagonist therapy in vivo.
Publication TypeJournal Article
Year of Publication2009
AuthorsTsibris AMN, Korber B, Arnaout R, Russ C, Lo C-C, Leitner T, Gaschen B, Theiler J, Paredes R, Su Z, Hughes MD, Gulick RM, Greaves W, Coakley E, Flexner C, Nusbaum C, Kuritzkes DR
JournalPLoS One
Volume4
Issue5
Paginatione5683
Date Published2009
ISSN1932-6203
KeywordsBase Sequence, Biological Evolution, CCR5 Receptor Antagonists, Entropy, HIV Infections, HIV-1, Humans, Likelihood Functions, Nucleic Acid Conformation, Piperazines, Pyrimidines, Reproducibility of Results, RNA, Viral, Selection, Genetic, Sequence Alignment, Sequence Analysis, DNA, Time Factors, Treatment Failure
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.

DOI10.1371/journal.pone.0005683
Alternate JournalPLoS ONE
PubMed ID19479085
PubMed Central IDPMC2682648
Grant ListK24 RR016482 / RR / NCRR NIH HHS / United States
P30 AI060354 / AI / NIAID NIH HHS / United States
P30 AI060354 / AI / NIAID NIH HHS / United States
R37 AI553537 / AI / NIAID NIH HHS / United States
T32 AI007387 / AI / NIAID NIH HHS / United States
U01 AI067854 / AI / NIAID NIH HHS / United States
U01 AI069472 / AI / NIAID NIH HHS / United States