Envelope residue 375 substitutions in simian-human immunodeficiency viruses enhance CD4 binding and replication in rhesus macaques

Hui Li, Shuyi Wang, Rui Kong, Wenge Ding, Fang Hua Lee, Zahra Parker, Eunlim Kim, Gerald H. Learn, Paul Hahn, Ben Policicchio, Egidio Brocca-Cofano, Claire Deleage, Xingpei Hao, Gwo Yu Chuang, Jason Gorman, Matthew Gardner, Mark G. Lewis, Theodora Hatziioannou, Sampa Santra, Cristian ApetreiIvona Pandrea, S. Munir Alam, Hua Xin Liao, Xiaoying Shen, Georgia D. Tomaras, Michael Farzan, Elena Chertova, Brandon F. Keele, Jacob D. Estes, Jeffrey D. Lifson, Robert W. Doms, David C. Montefiori, Barton F. Haynes, Joseph G. Sodroski, Peter D. Kwong, Beatrice H. Hahn, George M. Shaw

Research output: Contribution to journalArticlepeer-review

139 Scopus citations


Most simian-human immunodeficiency viruses (SHIVs) bearing envelope (Env) glycoproteins from primary HIV-1 strains fail to infect rhesus macaques (RMs). We hypothesized that inefficient Env binding to rhesus CD4 (rhCD4) limits virus entry and replication and could be enhanced by substituting naturally occurring simian immunodeficiency virus Env residues at position 375, which resides at a critical location in the CD4-binding pocket and is under strong positive evolutionary pressure across the broad spectrum of primate lentiviruses. SHIVs containing primary or transmitted/founder HIV-1 subtype A, B, C, or D Envs with genotypic variants at residue 375 were constructed and analyzed in vitro and in vivo. Bulky hydrophobic or basic amino acids substituted for serine-375 enhanced Env affinity for rhCD4, virus entry into cells bearing rhCD4, and virus replication in primary rhCD4 T cells without appreciably affecting antigenicity or antibodymediated neutralization sensitivity. Twenty-four RMs inoculated with subtype A, B, C, or D SHIVs all became productively infected with different Env375 variants - S, M, Y, H, W, or F - that were differentially selected in different Env backbones. Notably, SHIVs replicated persistently at titers comparable to HIV-1 in humans and elicited autologous neutralizing antibody responses typical of HIV-1. Seven animals succumbed to AIDS. These findings identify Env-rhCD4 binding as a critical determinant for productive SHIV infection in RMs and validate a novel and generalizable strategy for constructing SHIVs with Env glycoproteins of interest, including those that in humans elicit broadly neutralizing antibodies or bind particular Ig germ-line B-cell receptors.

Original languageEnglish (US)
Pages (from-to)E3413-E3422
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number24
StatePublished - Jun 14 2016
Externally publishedYes


  • CD4
  • HIV-1 envelope
  • SHIV

ASJC Scopus subject areas

  • General


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