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

Publication ,  Journal Article
Li, H; Wang, S; Kong, R; Ding, W; Lee, F-H; Parker, Z; Kim, E; Learn, GH; Hahn, P; Policicchio, B; Brocca-Cofano, E; Deleage, C; Hao, X ...
Published in: Proc Natl Acad Sci U S A
June 14, 2016

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 antibody-mediated 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.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

June 14, 2016

Volume

113

Issue

24

Start / End Page

E3413 / E3422

Location

United States

Related Subject Headings

  • env Gene Products, Human Immunodeficiency Virus
  • Virus Replication
  • Simian immunodeficiency virus
  • Simian Immunodeficiency Virus
  • Simian Acquired Immunodeficiency Syndrome
  • Mutation, Missense
  • Macaca mulatta
  • Humans
  • HIV-1
  • HIV Infections
 

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Li, H., Wang, S., Kong, R., Ding, W., Lee, F.-H., Parker, Z., … Shaw, G. M. (2016). Envelope residue 375 substitutions in simian-human immunodeficiency viruses enhance CD4 binding and replication in rhesus macaques. Proc Natl Acad Sci U S A, 113(24), E3413–E3422. https://doi.org/10.1073/pnas.1606636113
Li, Hui, Shuyi Wang, Rui Kong, Wenge Ding, Fang-Hua Lee, Zahra Parker, Eunlim Kim, et al. “Envelope residue 375 substitutions in simian-human immunodeficiency viruses enhance CD4 binding and replication in rhesus macaques.Proc Natl Acad Sci U S A 113, no. 24 (June 14, 2016): E3413–22. https://doi.org/10.1073/pnas.1606636113.
Li H, Wang S, Kong R, Ding W, Lee F-H, Parker Z, et al. Envelope residue 375 substitutions in simian-human immunodeficiency viruses enhance CD4 binding and replication in rhesus macaques. Proc Natl Acad Sci U S A. 2016 Jun 14;113(24):E3413–22.
Li, Hui, et al. “Envelope residue 375 substitutions in simian-human immunodeficiency viruses enhance CD4 binding and replication in rhesus macaques.Proc Natl Acad Sci U S A, vol. 113, no. 24, June 2016, pp. E3413–22. Pubmed, doi:10.1073/pnas.1606636113.
Li H, Wang S, Kong R, Ding W, Lee F-H, Parker Z, Kim E, Learn GH, Hahn P, Policicchio B, Brocca-Cofano E, Deleage C, Hao X, Chuang G-Y, Gorman J, Gardner M, Lewis MG, Hatziioannou T, Santra S, Apetrei C, Pandrea I, Alam SM, Liao H-X, Shen X, Tomaras GD, Farzan M, Chertova E, Keele BF, Estes JD, Lifson JD, Doms RW, Montefiori DC, Haynes BF, Sodroski JG, Kwong PD, Hahn BH, Shaw GM. Envelope residue 375 substitutions in simian-human immunodeficiency viruses enhance CD4 binding and replication in rhesus macaques. Proc Natl Acad Sci U S A. 2016 Jun 14;113(24):E3413–E3422.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

June 14, 2016

Volume

113

Issue

24

Start / End Page

E3413 / E3422

Location

United States

Related Subject Headings

  • env Gene Products, Human Immunodeficiency Virus
  • Virus Replication
  • Simian immunodeficiency virus
  • Simian Immunodeficiency Virus
  • Simian Acquired Immunodeficiency Syndrome
  • Mutation, Missense
  • Macaca mulatta
  • Humans
  • HIV-1
  • HIV Infections