|Title||A pièce de resistance: how HIV-1 escapes small molecule CCR5 inhibitors.|
|Publication Type||Journal Article|
|Year of Publication||2009|
|Authors||Moore JP, Kuritzkes DR|
|Journal||Curr Opin HIV AIDS|
|Date Published||2009 Mar|
|Keywords||Anti-HIV Agents, Cyclohexanes, Drug Resistance, Viral, HIV Envelope Protein gp120, HIV Fusion Inhibitors, HIV-1, Humans, Mutation, Missense, Piperazines, Pyrimidines, Receptors, CCR5, Triazoles|
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.
|Alternate Journal||Curr Opin HIV AIDS|
|PubMed Central ID||PMC2896203|
|Grant List||R01 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
Submitted by mam2155 on March 24, 2014 - 4:19pm