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Resistance of a human immunodeficiency virus type 1 isolate to a small molecule CCR5 inhibitor can involve sequence changes in both gp120 and gp41.

TitleResistance of a human immunodeficiency virus type 1 isolate to a small molecule CCR5 inhibitor can involve sequence changes in both gp120 and gp41.
Publication TypeJournal Article
Year of Publication2011
AuthorsAnastassopoulou CG, Ketas TJ, Depetris RS, Thomas AM, Klasse PJohan, Moore JP
JournalVirology
Volume413
Issue1
Pagination47-59
Date Published2011 Apr 25
ISSN1096-0341
KeywordsAmino Acid Sequence, Amino Acid Substitution, CCR5 Receptor Antagonists, Drug Resistance, Viral, HIV Envelope Protein gp120, HIV Envelope Protein gp41, HIV Infections, HIV-1, Humans, Molecular Sequence Data, Mutation, Missense, Piperazines, Pyrimidines, Sequence Alignment
Abstract

Here, we describe the genetic pathways taken by a human immunodeficiency virus type 1 (HIV-1) isolate, D101.12, to become resistant to the small molecule CCR5 inhibitor, vicriviroc (VCV), in vitro. Resistant D101.12 variants contained at least one substitution in the gp120 V3 region (H308P), plus one of two patterns of gp41 sequence changes involving the fusion peptide (FP) and a downstream residue: G514V+V535M or M518V+F519L+V535M. Studies of Env-chimeric and point-substituted viruses in peripheral blood mononuclear cells (PBMC) and TZM-bl cells showed that resistance can arise from the cooperative action of gp120 and gp41 changes, while retaining CCR5 usage. Modeling the VCV inhibition data from the two cell types suggests that D101.12 discriminates between high- and low-VCV affinity forms of CCR5 less than D1/85.16, a resistant virus with three FP substitutions.

DOI10.1016/j.virol.2010.12.052
Alternate JournalVirology
PubMed ID21356539
PubMed Central IDPMC3070043
Grant ListR01 AI041420 / AI / NIAID NIH HHS / United States
R01 AI041420-15 / AI / NIAID NIH HHS / United States
R01 AI41420 / AI / NIAID NIH HHS / United States

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