@article{426ddbd5bdb14b44a4bcd402ec7677bd,
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.",
keywords = "C4 domain, CD4bs, Clade C, Envelope, HIV-1, Neutralizing antibody, Recent infection, V3 loop",
author = "Rajesh Ringe and Deepak Sharma and Susan Zolla-Pazner and Sanjay Phogat and Arun Risbud and Madhuri Thakar and Ramesh Paranjape and Jayanta Bhattacharya",
note = "Funding Information: This work was primarily supported by extramural grants from the Department of Biotechnology ( BT/PR7829/MED/14/1133/2006 and BT/PR12853/MED/29/141/2009 ), Government of India to JB and partly by the Collaboration of AIDS Vaccine Discovery (CAVD) and Vaccine Immune Monitoring Consortium (VIMC) (Grant # 38619 ). SZP was supported by grants from the USA National Institutes of Health ( AI 36085, HL59725, and AI27747 ), from the Bill and Melinda Gates Foundation and from research funds from the USA Department of Veterans Affairs . We thank Prof Lynn Morris, National Institute of Communicable Diseases (NICD), Johannesburg, South Africa for the generous gift of the HIV+ plasma samples obtained from South African donors, Dr Paul Clapham, UMASS Medical School, Worcester, Massachusetts for the pSVIIIenv-SF162, pSVIIIenv-YU2, pSVIIIenv-JRFL plasmids, Dr David Montefiori, Duke University for RHPA4259.7 Env plasmid and Dr David Kabat, University of Portland, Oregon for HeLa (RC49) cell line. We thank Dr Wayne Koff, IAVI for providing us with PG9 and PG16 MAbs, Dr Dennis Burton, Scripps Research Institute, La Jolla, CA, USA for b12 MAb and Dr John Mascola, Vaccine Research Center, National Institute of Health, USA for VRC01 MAb. We are appreciative of the NIH AIDS Research Reagent Reference Program for providing many reagents including TZM-bl cells, anti-p24 MAb (18-H12-5C) and TAK-779 and 447-42D MAb used in this study. RR and DS are supported by the Senior Research Fellowships from the Council of Scientific and Industrial Research (CSIR) and University Grants Commission (UGC), Government of India respectively.",
year = "2011",
month = sep,
day = "30",
doi = "10.1016/j.virol.2011.07.015",
language = "English",
volume = "418",
pages = "123--132",
journal = "Virology",
issn = "0042-6822",
publisher = "Academic Press Inc.",
number = "2",
}