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Neutralizing antibody and anti-retroviral drug sensitivities of HIV-1 isolates resistant to small molecule CCR5 inhibitors.

TitleNeutralizing antibody and anti-retroviral drug sensitivities of HIV-1 isolates resistant to small molecule CCR5 inhibitors.
Publication TypeJournal Article
Year of Publication2008
AuthorsPugach P, Ketas TJ, Michael E, Moore JP
JournalVirology
Volume377
Issue2
Pagination401-7
Date Published2008 Aug 1
ISSN0042-6822
KeywordsAnti-HIV Agents, Antibodies, Viral, Drug Resistance, Viral, HIV Fusion Inhibitors, HIV-1, Humans, Neutralization Tests, Receptors, CCR5
Abstract

The small molecule CCR5 inhibitors are a new class of drugs for treating infection by human immunodeficiency virus type 1 (HIV-1). They act by binding to the CCR5 co-receptor and preventing its use during HIV-1-cell fusion. Escape mutants can be raised against CCR5 inhibitors in vitro and will arise when these drugs are used clinically. Here, we have assessed the responses of CCR5 inhibitor-resistant viruses to other anti-retroviral drugs that act by different mechanisms, and their sensitivities to neutralizing antibodies (NAbs). The rationale for the latter study is that the resistance pathway for CCR5 inhibitors involves changes in the HIV-1 envelope glycoproteins (Env), which are also targets for NAbs. The escape mutants CC101.19 and D1/85.16 were selected for resistance to AD101 and vicriviroc (VVC), respectively, from the primary R5 HIV-1 isolate CC1/85. Each escape mutant was cross-resistant to other small molecule CCR5 inhibitors (aplaviroc, maraviroc, VVC, AD101 and CMPD 167), but sensitive to protein ligands of CCR5: the modified chemokine PSC-RANTES and the humanized MAb PRO-140. The resistant viruses also retained wild-type sensitivity to the nucleoside reverse transcriptase inhibitor (RTI) zidovudine, the non-nucleoside RTI nevirapine, the protease inhibitor atazanavir and other attachment and fusion inhibitors that act independently of CCR5 (BMS-806, PRO-542 and enfuvirtide). Of note is that the escape mutants were more sensitive than the parental CC1/85 isolate to a subset of neutralizing monoclonal antibodies and to some sera from HIV-1-infected people, implying that sequence changes in Env that confer resistance to CCR5 inhibitors can increase the accessibility of some NAb epitopes. The need to preserve NAb resistance may therefore be a constraint upon how escape from CCR5 inhibitors occurs in vivo.

DOI10.1016/j.virol.2008.04.032
Alternate JournalVirology
PubMed ID18519143
PubMed Central IDPMC2528836
Grant ListAI36082 / AI / NIAID NIH HHS / United States
AI41420 / AI / NIAID NIH HHS / United States
R01 AI041420-13 / AI / NIAID NIH HHS / United States
R01 AI041420-17 / AI / NIAID NIH HHS / United States
R37 AI036082-15 / AI / NIAID NIH HHS / United States
R37 AI040877-15 / AI / NIAID NIH HHS / United States
T32 AI07621 / AI / NIAID NIH HHS / United States

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