title: Transmitted/founder and chronic HIV-1 envelope proteins are distinguished by differential utilization of CCR5.
abstract: Infection by HIV-1 most often results from the successful transmission and propagation of a single virus variant, termed the transmitted/founder (T/F) virus. Here, we compared the attachment and entry properties of envelope (Env) glycoproteins from T/F and chronic control (CC) viruses. Using a panel of 40 T/F and 47 CC Envs, all derived by single genome amplification, we found that 52% of clade C and B CC Envs exhibited partial resistance to the CCR5 antagonist maraviroc (MVC) on cells expressing high levels of CCR5, while only 15% of T/F Envs exhibited this same property. Moreover, subtle differences in the magnitude with which MVC inhibited infection on cells expressing low levels of CCR5, including primary CD4(+) T cells, were highly predictive of MVC resistance when CCR5 expression levels were high. These results are consistent with previous observations showing a greater sensitivity of T/F Envs to MVC inhibition on cells expressing very high levels of CCR5 and indicate that CC Envs are often capable of recognizing MVC-bound CCR5, albeit inefficiently on cells expressing physiologic levels of CCR5. When CCR5 expression levels are high, this phenotype becomes readily detectable. The utilization of drug-bound CCR5 conformations by many CC Envs was seen with other CCR5 antagonists, with replication-competent viruses, and did not obviously correlate with other phenotypic traits. The striking ability of clade C and B CC Envs to use MVC-bound CCR5 relative to T/F Envs argues that the more promiscuous use of CCR5 by these Env proteins is selected against at the level of virus transmission and is selected for during chronic infection.
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Zahra F
authors.initials: ZF
authors.lastname: Parker
authors.forename: Shilpa S
authors.initials: SS
authors.lastname: Iyer
authors.forename: Craig B
authors.initials: CB
authors.lastname: Wilen
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Parrish
authors.forename: Kelechi C
authors.initials: KC
authors.lastname: Chikere
authors.forename: Fang-Hua
authors.initials: FH
authors.lastname: Lee
authors.forename: Chuka A
authors.initials: CA
authors.lastname: Didigu
authors.forename: Reem
authors.initials: R
authors.lastname: Berro
authors.forename: Per Johan
authors.initials: PJ
authors.lastname: Klasse
authors.forename: Benhur
authors.initials: B
authors.lastname: Lee
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
authors.forename: George M
authors.initials: GM
authors.lastname: Shaw
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.forename: Robert W
authors.initials: RW
authors.lastname: Doms
mesh_terms: D065100:CCR5 Receptor Antagonists; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D003510:Cyclohexanes / Q000494:pharmacology*; D057809:HEK293 Cells; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D000077592:Maraviroc; D019713:Receptors, CCR5 / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology*; D053585:Virus Attachment; D053586:Virus Internalization; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology* / Q000378:metabolism*
chemical_list: D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D019713:Receptors, CCR5; D014230:Triazoles; D054299:env Gene Products, Human Immunodeficiency Virus; D000077592:Maraviroc