Differential use of CCR5 by HIV-1 clinical isolates resistant to small-molecule CCR5 antagonists.

TitleDifferential use of CCR5 by HIV-1 clinical isolates resistant to small-molecule CCR5 antagonists.
Publication TypeJournal Article
Year of Publication2012
AuthorsHenrich TJ, Lewine NRP, Lee S-H, Rao SSP, Berro R, Gulick RM, Moore JP, Tsibris AMN, Kuritzkes DR
JournalAntimicrob Agents Chemother
Volume56
Issue4
Pagination1931-5
Date Published2012 Apr
ISSN1098-6596
KeywordsAmino Acid Sequence, Amino Acid Substitution, Anti-HIV Agents, Antibodies, Blocking, Antibodies, Monoclonal, CCR5 Receptor Antagonists, Cyclohexanes, Drug Resistance, Viral, HIV Fusion Inhibitors, HIV Infections, HIV-1, Humans, Piperazines, Pyrimidines, Receptors, CCR5, Triazoles
Abstract

How HIV-1 resistant to small-molecule CCR5 antagonists uses the coreceptor for entry has been studied in a limited number of isolates. We characterized dependence on the N terminus (NT) and the second extracellular loop (ECL2) of CCR5 of three vicriviroc (VCV)-resistant clinical isolates broadly cross-resistant to other CCR5 antagonists. Pseudoviruses were constructed to assess CCR5 use by VCV-sensitive and -resistant envelopes of subtype B and C viruses. We determined the extent of entry inhibition by monoclonal antibodies (MAbs) directed against the NT and ECL2 in the presence and absence of VCV and the capacity of these pseudoviruses to use CCR5 mutants that contained scanning alanine substitutions in the CCR5 NT and ECL2 domains. Sensitive and resistant viruses were completely and competitively inhibited by the ECL2-specific MAb 2D7, whereas the NT-specific MAb CTC5 led to partial noncompetitive inhibition. VCV-resistant clones showed greater sensitivity to 2D7 than VCV-sensitive clones, but in the presence of saturating VCV concentrations, the 2D7 susceptibilities of two VCV-resistant viruses were similar to that of VCV-sensitive virus. The entry of VCV-sensitive and -resistant isolates was impaired to differing degrees by alanine mutations in CCR5; substitutions in NT had the greatest effect on viral entry. HIV-1 clinical isolates broadly resistant to CCR5 antagonists demonstrated significant heterogeneity in their use of CCR5. This heterogeneity makes it difficult to draw general conclusions about the relationship between patterns of CCR5 antagonist resistance and the use of specific CCR5 domains for entry.

DOI10.1128/AAC.06061-11
Alternate JournalAntimicrob. Agents Chemother.
PubMed ID22252820
PubMed Central IDPMC3318367
Grant ListAI-68636 / AI / NIAID NIH HHS / United States
K08 AI081547 / AI / NIAID NIH HHS / United States
K24 AI-51966 / AI / NIAID NIH HHS / United States
K24 AI051966 / AI / NIAID NIH HHS / United States
K24 RR016482 / RR / NCRR NIH HHS / United States
P30 AI060354 / AI / NIAID NIH HHS / United States
R01 AI041420 / AI / NIAID NIH HHS / United States
R01 AI041420 / AI / NIAID NIH HHS / United States
R37 AI055357 / AI / NIAID NIH HHS / United States
R37 AI055357 / AI / NIAID NIH HHS / United States
T32 AI007387 / AI / NIAID NIH HHS / United States
UL1 RR 025758 / RR / NCRR NIH HHS / United States
UL1 RR025758 / RR / NCRR NIH HHS / United States