title: Association of enhanced HIV-1 neutralization by a single Y681H substitution in gp41 with increased gp120-CD4 interaction and macrophage infectivity.
abstract: HIV-1 variants that show unusual sensitivity to autologous antibodies due to presence of critical neutralization signatures would likely contribute towards rational envelope based HIV-1 vaccine design. In the present study, we found that presence of a naturally occurring H681 in gp41 membrane proximal external region (MPER) of a clade C envelope (Env) obtained from a recently infected Indian patient conferred increased sensitivity to autologous and heterologous plasma antibodies. Furthermore, Env-pseudotyped viruses expressing H681 showed increased sensitivity to soluble CD4, b12 and 4E10 monoclonal antibodies both in related and unrelated Envs and was corroborated with increased Env susceptibility and binding to cellular CD4 as well as with prolonged exposure of MPER epitopes. The increased gp120-CD4 interaction was further associated with relative exposure of CD4-induced epitopes and macrophage infectivity. In summary, our data indicate that Y681H substitution exposes neutralizing epitopes in CD4bs and MPER towards comprehensive interference in HIV-1 entry.
authors.affiliation: Department of Molecular Virology, National AIDS Research Institute, Indian Council of Medical Research, Bhosari, Pune, India.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Ringe
authors.forename: Jayanta
authors.initials: J
authors.lastname: Bhattacharya
mesh_terms: D019943:Amino Acid Substitution; D057134:Antibodies, Neutralizing / Q000097:blood; D015704:CD4 Antigens / Q000276:immunology; D015483:HIV Antibodies / Q000097:blood; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015700:HIV Envelope Protein gp41 / Q000235:genetics* / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology* / Q000472:pathogenicity; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000821:virology; D017201:Virus Shedding
chemical_list: D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; C514793:gp120 protein, Human immunodeficiency virus 1; C514787:gp41 protein, Human immunodeficiency virus 1