title: A single amino acid substitution in the C4 region in gp120 confers enhanced neutralization of HIV-1 by modulating CD4 binding sites and V3 loop.
abstract: Identification of vulnerability in the HIV-1 envelope (Env) will aid in Env-based vaccine design. We recently found an HIV-1 clade C Env clone (4-2.J45) amplified from a recently infected Indian patient showing exceptional neutralization sensitivity to autologous plasma in contrast to other autologous Envs obtained at the same time point. By constructing chimeric Envs and fine mapping between sensitive and resistant Env clones, we found that substitution of highly conserved isoleucine (I) with methionine (M) (ATA to ATG) at position 424 in the C4 domain conferred enhanced neutralization sensitivity of Env-pseudotyped viruses to autologous and heterologous plasma antibodies. When tested against monoclonal antibodies targeting different sites in gp120 and gp41, Envs expressing M424 showed significant sensitivity to anti-V3 monoclonal antibodies and modestly to sCD4 and b12. Substitution of I424M in unrelated Envs also showed similar neutralization phenotype, indicating that M424 in C4 region induces exposure of neutralizing epitopes particularly in CD4 binding sites and V3 loop.
authors.affiliation: Department of Molecular Virology, National AIDS Research Institute, Pune, India.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Ringe
authors.forename: Deepak
authors.initials: D
authors.lastname: Sharma
authors.forename: Susan
authors.initials: S
authors.lastname: Zolla-Pazner
authors.forename: Sanjay
authors.initials: S
authors.lastname: Phogat
authors.forename: Arun
authors.initials: A
authors.lastname: Risbud
authors.forename: Madhuri
authors.initials: M
authors.lastname: Thakar
authors.forename: Ramesh
authors.initials: R
authors.lastname: Paranjape
authors.forename: Jayanta
authors.initials: J
authors.lastname: Bhattacharya
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000914:Antibodies, Viral; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D015967:Gene Expression Regulation, Viral; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D015497:HIV-1 / Q000145:classification / Q000235:genetics*; D008715:Methionine; D008969:Molecular Sequence Data; D053585:Virus Attachment
chemical_list: D000914:Antibodies, Viral; D015699:HIV Envelope Protein gp120; C514793:gp120 protein, Human immunodeficiency virus 1; D008715:Methionine