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Inefficient entry of vicriviroc-resistant HIV-1 via the inhibitor-CCR5 complex at low cell surface CCR5 densities.

TitleInefficient entry of vicriviroc-resistant HIV-1 via the inhibitor-CCR5 complex at low cell surface CCR5 densities.
Publication TypeJournal Article
Year of Publication2009
AuthorsPugach P, Ray N, Klasse PJohan, Ketas TJ, Michael E, Doms RW, Lee B, Moore JP
JournalVirology
Volume387
Issue2
Pagination296-302
Date Published2009 May 10
ISSN1096-0341
KeywordsCCR5 Receptor Antagonists, Cell Line, Drug Resistance, Viral, HIV Infections, HIV-1, Humans, Piperazines, Pyrimidines, Receptors, CCR5, Virus Attachment, Virus Internalization
Abstract

HIV-1 variants resistant to small molecule CCR5 inhibitors such as vicriviroc (VVC) have modified Env complexes that can use both the inhibitor-bound and -free forms of the CCR5 co-receptor to enter target cells. However, entry via the inhibitor-CCR5 complex is inefficient in some, but not all, cell types, particularly cell lines engineered to express CCR5. We investigated the effect of increasing CCR5 expression, and hence the density of the inhibitor-CCR5 complex when a saturating inhibitor (VVC) concentration was present, by using 293-Affinofile cells, in which CCR5 expression is up-regulated by the transcriptional activator, ponasterone. When CCR5 expression was low, the resistant virus entered the target cells to a lesser extent when VVC was present than absent. However, at a higher CCR5 level, there was much less entry inhibition at a constant, saturating VVC concentration. We conclude that the relative decrease in entry of a VVC-resistant virus in some cell types results from its less efficient use of the VVC-CCR5 complex, and that increasing the CCR5 expression level can compensate for this inefficiency.

DOI10.1016/j.virol.2009.02.044
Alternate JournalVirology
PubMed ID19303620
PubMed Central IDPMC2674391
Grant ListR01 AI041420 / AI / NIAID NIH HHS / United States
R01 AI041420-13 / AI / NIAID NIH HHS / United States
R01 AI40880 / AI / NIAID NIH HHS / United States
R01 AI41420 / AI / NIAID NIH HHS / United States
R37 AI040877 / AI / NIAID NIH HHS / United States
T32 AI07621 / AI / NIAID NIH HHS / United States

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