title: Impact of the Maraviroc-Resistant Mutation M434I in the C4 Region of HIV-1 gp120 on Sensitivity to Antibody-Mediated Neutralization.
abstract: We previously reported that a maraviroc (MVC)-resistant human immunodeficiency virus type 1variant, generated using in vitro selection, exhibited high sensitivity to several neutralizing monoclonal antibodies (NMAbs) and autologous plasma IgGs. The MVC-resistant variant acquired 4 sequential mutations in gp120: T297I, M434I, V200I, and K305R. In this study, we examined the mutation most responsible for conferring enhanced neutralization sensitivity of the MVC-resistant variant to several NMAbs and autologous plasma IgGs. The virus with the first resistant mutation, T297I, was sensitive to all NMAbs, whereas the passage control virus was not. The neutralization sensitivity of the variant greatly increased following its acquisition of the second mutation, M434I, in the C4 region. The M434I mutation conferred the greatest neutralizing sensitivity among the 4 MVC-resistant mutations. Additionally, the single M434I mutation was sufficient for the enhanced neutralization of the virus by NMAbs, autologous plasma IgGs, and heterologous sera relative to that of the parental virus.
authors.affiliation: Center for AIDS Research, Kumamoto University.
authors.forename: Samatchaya
authors.initials: S
authors.lastname: Boonchawalit
authors.forename: Shigeyoshi
authors.initials: S
authors.lastname: Harada
authors.forename: Noriko
authors.initials: N
authors.lastname: Shirai
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Gatanaga
authors.forename: Shinichi
authors.initials: S
authors.lastname: Oka
authors.forename: Shuzo
authors.initials: S
authors.lastname: Matsushita
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Yoshimura
mesh_terms: D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000302:isolation & purification / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000096:biosynthesis / Q000302:isolation & purification / Q000494:pharmacology*; D000914:Antibodies, Viral / Q000096:biosynthesis / Q000302:isolation & purification / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000821:virology; D002460:Cell Line; D003510:Cyclohexanes / Q000494:pharmacology; D024882:Drug Resistance, Viral / Q000235:genetics; D015870:Gene Expression; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D023581:HIV Fusion Inhibitors / Q000494:pharmacology; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007106:Immune Sera / Q000737:chemistry; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000302:isolation & purification / Q000494:pharmacology*; D000077592:Maraviroc; D009154:Mutation; D009500:Neutralization Tests; D019713:Receptors, CCR5 / Q000235:genetics / Q000276:immunology; D014230:Triazoles / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; C584933:CCR5 protein, human; D003510:Cyclohexanes; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; D007106:Immune Sera; D007074:Immunoglobulin G; D019713:Receptors, CCR5; D014230:Triazoles; D000077592:Maraviroc