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Multiple CCR5 conformations on the cell surface are used differentially by human immunodeficiency viruses resistant or sensitive to CCR5 inhibitors.

TitleMultiple CCR5 conformations on the cell surface are used differentially by human immunodeficiency viruses resistant or sensitive to CCR5 inhibitors.
Publication TypeJournal Article
Year of Publication2011
AuthorsBerro R, Klasse PJohan, Lascano D, Flegler A, Nagashima KA, Sanders RW, Sakmar TP, Hope TJ, Moore JP
JournalJ Virol
Volume85
Issue16
Pagination8227-40
Date Published2011 Aug
ISSN1098-5514
KeywordsAnti-HIV Agents, Antibodies, Monoclonal, CD4-Positive T-Lymphocytes, Cell Line, Cell Membrane, Cyclohexanes, Drug Resistance, Viral, Epitopes, Flow Cytometry, HEK293 Cells, HIV Envelope Protein gp120, HIV Envelope Protein gp41, HIV-1, Humans, Membrane Microdomains, Microscopy, Fluorescence, Piperazines, Pyrimidines, Receptors, CCR5, Triazoles, Viral Fusion Proteins, Virus Internalization
Abstract

Resistance to small-molecule CCR5 inhibitors arises when HIV-1 variants acquire the ability to use inhibitor-bound CCR5 while still recognizing free CCR5. Two isolates, CC101.19 and D1/85.16, became resistant via four substitutions in the gp120 V3 region and three in the gp41 fusion peptide (FP), respectively. The binding characteristics of a panel of monoclonal antibodies (MAbs) imply that several antigenic forms of CCR5 are expressed at different levels on the surfaces of U87-CD4-CCR5 cells and primary CD4(+) T cells, in a cell-type-dependent manner. CCR5 binding and HIV-1 infection inhibition experiments suggest that the two CCR5 inhibitor-resistant viruses altered their interactions with CCR5 in different ways. As a result, both mutants became generally more sensitive to inhibition by CCR5 MAbs, and the FP mutant is specifically sensitive to a MAb that stains discrete cell surface clusters of CCR5 that may correspond to lipid rafts. We conclude that some MAbs detect different antigenic forms of CCR5 and that inhibitor-sensitive and -resistant viruses can use these CCR5 forms differently for entry in the presence or absence of CCR5 inhibitors.

DOI10.1128/JVI.00767-11
Alternate JournalJ. Virol.
PubMed ID21680525
PubMed Central IDPMC3147974
Grant ListR01 AI052051 / AI / NIAID NIH HHS / United States
R01 AI41420 / AI / NIAID NIH HHS / United States

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