title: Inefficient entry of vicriviroc-resistant HIV-1 via the inhibitor-CCR5 complex at low cell surface CCR5 densities.
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.
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY, USA.
authors.forename: Pavel
authors.initials: P
authors.lastname: Pugach
authors.forename: Neelanjana
authors.initials: N
authors.lastname: Ray
authors.forename: Per Johan
authors.initials: PJ
authors.lastname: Klasse
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Ketas
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Michael
authors.forename: Robert W
authors.initials: RW
authors.lastname: Doms
authors.forename: Benhur
authors.initials: B
authors.lastname: Lee
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
mesh_terms: D065100:CCR5 Receptor Antagonists; D002460:Cell Line; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D019713:Receptors, CCR5 / Q000502:physiology*; D053585:Virus Attachment; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D065100:CCR5 Receptor Antagonists; D010879:Piperazines; D011743:Pyrimidines; D019713:Receptors, CCR5; C486781:vicriviroc