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

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.

journal_name

Curr Opin HIV AIDS

authors

Moore JP,Kuritzkes DR

doi

10.1097/COH.0b013e3283223d46

subject

Has Abstract

pub_date

2009-03-01 00:00:00

pages

118-24

issue

2

eissn

1746-630X

issn

1746-6318

pii

01222929-200903000-00008

journal_volume

4

pub_type

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