title: Use of G-protein-coupled and -uncoupled CCR5 receptors by CCR5 inhibitor-resistant and -sensitive human immunodeficiency virus type 1 variants.
abstract: Small-molecule CCR5 inhibitors such as vicriviroc (VVC) and maraviroc (MVC) are allosteric modulators that impair HIV-1 entry by stabilizing a CCR5 conformation that the virus recognizes inefficiently. Viruses resistant to these compounds are able to bind the inhibitor-CCR5 complex while also interacting with the free coreceptor. CCR5 also interacts intracellularly with G proteins, as part of its signal transduction functions, and this process alters its conformation. Here we investigated whether the action of VVC against inhibitor-sensitive and -resistant viruses is affected by whether or not CCR5 is coupled to G proteins such as Gαi. Treating CD4(+) T cells with pertussis toxin to uncouple the Gαi subunit from CCR5 increased the potency of VVC against the sensitive viruses and revealed that VVC-resistant viruses use the inhibitor-bound form of Gαi-coupled CCR5 more efficiently than they use uncoupled CCR5. Supportive evidence was obtained by expressing a signaling-deficient CCR5 mutant with an impaired ability to bind to G proteins, as well as two constitutively active mutants that activate G proteins in the absence of external stimuli. The implication of these various studies is that the association of intracellular domains of CCR5 with the signaling machinery affects the conformation of the external and transmembrane domains and how they interact with small-molecule inhibitors of HIV-1 entry.
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Reem
authors.initials: R
authors.lastname: Berro
authors.forename: Anila
authors.initials: A
authors.lastname: Yasmeen
authors.forename: Ravinder
authors.initials: R
authors.lastname: Abrol
authors.forename: Bartosz
authors.initials: B
authors.lastname: Trzaskowski
authors.forename: Sarya
authors.initials: S
authors.lastname: Abi-Habib
authors.forename: Amy
authors.initials: A
authors.lastname: Grunbeck
authors.forename: Danny
authors.initials: D
authors.lastname: Lascano
authors.forename: William A
authors.initials: WA
authors.lastname: Goddard
authors.forename: Per Johan
authors.initials: PJ
authors.lastname: Klasse
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Sakmar
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology; D065100:CCR5 Receptor Antagonists; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology; D002460:Cell Line; D003510:Cyclohexanes / Q000494:pharmacology; D024882:Drug Resistance, Viral; D019204:GTP-Binding Proteins / Q000378:metabolism*; D057809:HEK293 Cells / Q000821:virology; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000145:classification / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000077592:Maraviroc; D037342:Pertussis Toxin / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014230:Triazoles / Q000494:pharmacology; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D023581:HIV Fusion Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D019713:Receptors, CCR5; D014230:Triazoles; D054299:env Gene Products, Human Immunodeficiency Virus; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D000077592:Maraviroc; C486781:vicriviroc