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

Athe M.N. Tsibris, Bette Korber, Ramy Arnaout, Carsten Russ, Chien Chi Lo, Thomas Leitner, Brian Gaschen, James Theiler, Roger Paredes, Zhaohui Su, Michael D. Hughes, Roy M. Gulick, Wayne Greaves, Eoin Coakley, Charles Flexner, Chad Nusbaum, Daniel R. Kuritzkes

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    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. © 2009 Tsibris et al.
    Original languageEnglish
    Article numbere5683
    JournalPLoS ONE
    Volume4
    Issue number5
    DOIs
    Publication statusPublished - 25 May 2009

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  • Cite this

    Tsibris, A. M. N., Korber, B., Arnaout, R., Russ, C., Lo, C. C., Leitner, T., Gaschen, B., Theiler, J., Paredes, R., Su, Z., Hughes, M. D., Gulick, R. M., Greaves, W., Coakley, E., Flexner, C., Nusbaum, C., & Kuritzkes, D. R. (2009). Quantitative deep sequencing reveals dynamic HIV-1 escape and large population shifts during CCR5 antagonist therapy in vivo. PLoS ONE, 4(5), [e5683]. https://doi.org/10.1371/journal.pone.0005683