Evolution of CCR5 antagonist resistance in an HIV-1 subtype C clinical isolate.

TitleEvolution of CCR5 antagonist resistance in an HIV-1 subtype C clinical isolate.
Publication TypeJournal Article
Year of Publication2010
AuthorsHenrich TJ, Tsibris AMN, Lewine NRP, Konstantinidis I, Leopold KE, Sagar M, Kuritzkes DR
JournalJ Acquir Immune Defic Syndr
Volume55
Issue4
Pagination420-7
Date Published2010 Dec
ISSN1944-7884
KeywordsAmides, Amino Acid Sequence, Anti-HIV Agents, CCR5 Receptor Antagonists, Cyclohexanes, Drug Resistance, Viral, Evolution, Molecular, HIV Envelope Protein gp120, HIV Infections, HIV-1, Humans, Microbial Sensitivity Tests, Molecular Sequence Data, Mutation, Peptide Fragments, Piperazines, Pyrimidines, Quaternary Ammonium Compounds, Receptors, CCR5, Triazoles
Abstract

OBJECTIVES: We previously reported vicriviroc (VCV) resistance in an HIV-infected subject and used deep sequencing and clonal analyses to track the evolution of V3 sequence forms over 28 weeks of therapy. Here, we test the contribution of gp120 mutations to CCR5 antagonist resistance and investigate why certain minority V3 variants emerged as the dominant species under drug pressure.

METHODS: Nineteen site-directed HIV-1 mutants were generated that contained gp120 VCV resistance mutations. Viral sensitivities to VCV, maraviroc, TAK-779, and HGS004 were determined.

RESULTS: Three patterns of susceptibilities were observed as follows: sigmoid inhibition curves with 50% inhibitory concentration similar to pretreatment virus [07J-week 0 (W0)], single mutants with decreased 50% inhibitory concentrations compared with 07J-W0, and mutants that contained ≥5 of 7 VCV resistance mutations with flattened inhibition curves and decreased or negative percent maximal inhibition. Substitutions such as S306P, which sensitized virus to CCR5 antagonists when present as single mutations, were not detected in the baseline virus population but were necessary for maximal resistance when incorporated into V3 backbones that included preexisting VCV resistance mutations.

CONCLUSIONS: CCR5 antagonist resistance was reproduced only when a majority of V3 mutations were present. Minority V3 loop variants may serve as a scaffold upon which additional mutations lead to complete VCV resistance.

DOI10.1097/QAI.0b013e3181f25574
Alternate JournalJ. Acquir. Immune Defic. Syndr.
PubMed ID20856130
PubMed Central IDPMC3070184
Grant ListAI07387-19 / AI / NIAID NIH HHS / United States
K08 AI081547 / AI / NIAID NIH HHS / United States
K24 RR016482 / RR / NCRR NIH HHS / United States
K24 RR016482 / RR / NCRR NIH HHS / United States
K24 RR016482-10 / RR / NCRR NIH HHS / United States
P30 AI060354 / AI / NIAID NIH HHS / United States
R01 AI077473 / AI / NIAID NIH HHS / United States
R37 AI055357 / AI / NIAID NIH HHS / United States
R37 AI055357-09 / AI / NIAID NIH HHS / United States
R37 AI553537 / AI / NIAID NIH HHS / United States
T32 AI007387 / AI / NIAID NIH HHS / United States