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A pièce de resistance: how HIV-1 escapes small molecule CCR5 inhibitors.

TitleA pièce de resistance: how HIV-1 escapes small molecule CCR5 inhibitors.
Publication TypeJournal Article
Year of Publication2009
AuthorsMoore JP, Kuritzkes DR
JournalCurr Opin HIV AIDS
Volume4
Issue2
Pagination118-24
Date Published2009 Mar
ISSN1746-6318
KeywordsAnti-HIV Agents, Cyclohexanes, Drug Resistance, Viral, HIV Envelope Protein gp120, HIV Fusion Inhibitors, HIV-1, Humans, Mutation, Missense, Piperazines, Pyrimidines, Receptors, CCR5, Triazoles
Abstract

PURPOSE OF REVIEW: Small molecule inhibitors targeting the CCR5 coreceptor represent a new class of drugs for treating HIV-1 infection. Maraviroc has received regulatory approvals, and vicriviroc is in phase 3 trials. Understanding how resistance to these drugs develops and is diagnosed is essential to guide clinical practice. We review what has been learned from in-vitro resistance studies, and how this relates to what is being seen, or can be anticipated, in clinical studies.

RECENT FINDINGS: The principal resistance pathway in vitro involves continued use of CCR5 in an inhibitor-insensitive manner; the resistant viruses recognize the inhibitor-CCR5 complex, as well as free CCR5. Switching to use the CXCR4 coreceptor is rare. The principal genetic pathway involves accumulating 2-4 sequence changes in the gp120 V3 region, but a non-V3 pathway is also known. The limited information available from clinical studies suggests that a similar escape process is followed in vivo. However, the most common change associated with virologic failure involves expansion of pre-existing, CXCR4-using viruses that are insensitive to CCR5 inhibitors.

SUMMARY: HIV-1 escapes small molecule CCR5 inhibitors by continuing to use CCR5 in an inhibitor-insensitive manner, or evades them by expanding naturally insensitive, CXCR4-using variants.

DOI10.1097/COH.0b013e3283223d46
Alternate JournalCurr Opin HIV AIDS
PubMed ID19339950
PubMed Central IDPMC2896203
Grant ListR01 AI 41420 / AI / NIAID NIH HHS / United States
R01 AI041420-12 / AI / NIAID NIH HHS / United States
R01 AI041420-17 / AI / NIAID NIH HHS / United States
R37 AI 55357 / AI / NIAID NIH HHS / United States

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