title: The magnitude of HIV-1 resistance to the CCR5 antagonist maraviroc may impart a differential alteration in HIV-1 tropism for macrophages and T-cell subsets.
abstract: Human immunodeficiency virus type 1 (HIV-1) resistance to CCR5 antagonists, including maraviroc (MVC), results from alterations in the HIV-1 envelope glycoproteins (Env) enabling recognition of antagonist-bound CCR5. Here, we characterized tropism alterations for CD4+ T-cell subsets and macrophages by Envs from two subjects who developed MVC resistance in vivo, which displayed either relatively efficient or inefficient recognition of MVC-bound CCR5. We show that MVC-resistant Env with efficient recognition of drug-bound CCR5 displays a tropism shift for CD4+ T-cell subsets associated with increased infection of central memory T-cells and reduced infection of effector memory and transitional memory T-cells, and no change in macrophage infectivity. In contrast, MVC-resistant Env with inefficient recognition of drug-bound CCR5 displays no change in tropism for CD4+ T-cell subsets, but exhibits a significant reduction in macrophage infectivity. The pattern of HIV-1 tropism alterations for susceptible cells may therefore be variable in subjects with MVC resistance.
authors.affiliation: Center for Virology, Burnet Institute, Melbourne, VIC, Australia.
authors.forename: Jacqueline K
authors.initials: JK
authors.lastname: Flynn
authors.forename: Geza
authors.initials: G
authors.lastname: Paukovics
authors.forename: Miranda S
authors.initials: MS
authors.lastname: Moore
authors.forename: Anne
authors.initials: A
authors.lastname: Ellett
authors.forename: Lachlan R
authors.initials: LR
authors.lastname: Gray
authors.forename: Renee
authors.initials: R
authors.lastname: Duncan
authors.forename: Hamid
authors.initials: H
authors.lastname: Salimi
authors.forename: Becky
authors.initials: B
authors.lastname: Jubb
authors.forename: Mike
authors.initials: M
authors.lastname: Westby
authors.forename: Damian F J
authors.initials: DF
authors.lastname: Purcell
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Lewin
authors.forename: Benhur
authors.initials: B
authors.lastname: Lee
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Churchill
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gorry
authors.forename: Michael
authors.initials: M
authors.lastname: Roche
mesh_terms: D065100:CCR5 Receptor Antagonists; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D002460:Cell Line; D003510:Cyclohexanes / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000472:pathogenicity*; D006801:Humans; D008264:Macrophages / Q000821:virology*; D000077592:Maraviroc; D016176:T-Lymphocyte Subsets / Q000821:virology; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; D014230:Triazoles; D000077592:Maraviroc