Impact of the Maraviroc-Resistant Mutation M434I in the C4 Region of HIV-1 gp120 on Sensitivity to Antibody-Mediated Neutralization

Abstract

SUMMARY: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.

Higher Genetic Diversity and Viral Evolution in Key Regions of the Envelope Gene Are Associated with Broader Neutralizing Antibody Responses: a Report of Two Chronic HIV Infected Cases

“…Evolution of sites targeted by known bnAbs: It is believed that the neutralization activities of some bnAbs against viruses depend on amino acids or the PNGS at some key sites of the envelop proteins (21,(23)(24)(25)(26)(27). In HA172 and HA084, the polymorphisms and evolution on amino acids sites targeted by V1V2-glycan and CD4bs bnAbs were different.…”