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

Proceedings of the National Academy of Sciences - PNAS, 2016-06, Vol.113 (24), p.E3413-E3422 [Peer Reviewed Journal]

Volumes 1–89 and 106–113, copyright as a collective work only; author(s) retains copyright to individual articles ;ISSN: 0027-8424 ;EISSN: 1091-6490 ;DOI: 10.1073/pnas.1606636113 ;PMID: 27247400

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Title:
Envelope residue 375 substitutions in simian–human immunodeficiency viruses enhance CD4 binding and replication in rhesus macaques
Author: Li, Hui ; Wang, Shuyi ; Kong, Rui ; Ding, Wenge ; Lee, Fang-Hua ; Parker, Zahra ; Kim, Eunlim ; Learn, Gerald H. ; Hahn, Paul ; Policicchio, Ben ; Brocca-Cofano, Egidio ; Deleage, Claire ; Hao, Xingpei ; Chuang, Gwo-Yu ; Gorman, Jason ; Gardner, Matthew ; Lewis, Mark G. ; Hatziioannou, Theodora ; Santra, Sampa ; Apetrei, Cristian ; Pandrea, Ivona ; Alam, S. Munir ; Liao, Hua-Xin ; Shen, Xiaoying ; Tomaras, Georgia D. ; Farzan, Michael ; Chertova, Elena ; Keele, Brandon F. ; Estes, Jacob D. ; Lifson, Jeffrey D. ; Doms, Robert W. ; Montefiori, David C. ; Haynes, Barton F. ; Sodroski, Joseph G. ; Kwong, Peter D. ; Hahn, Beatrice H. ; Shaw, George M.
Subjects: Amino Acid Substitution ; Animals ; Binding sites ; Biological Sciences ; CD4 Antigens - metabolism ; env Gene Products, Human Immunodeficiency Virus - genetics ; env Gene Products, Human Immunodeficiency Virus - metabolism ; Genotype & phenotype ; Glycoproteins ; HIV ; HIV Infections - genetics ; HIV Infections - metabolism ; HIV-1 - physiology ; Human immunodeficiency virus ; Human immunodeficiency virus 1 ; Humans ; Lentivirus ; Macaca mulatta ; Monkeys & apes ; Mutation, Missense ; PNAS Plus ; Retroviridae ; Simian Acquired Immunodeficiency Syndrome - genetics ; Simian Acquired Immunodeficiency Syndrome - metabolism ; Simian immunodeficiency virus ; Simian Immunodeficiency Virus - physiology ; Virus Replication - genetics
Is Part Of: Proceedings of the National Academy of Sciences - PNAS, 2016-06, Vol.113 (24), p.E3413-E3422
Description: 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.
Publisher: United States: National Academy of Sciences
Language: English
Identifier: ISSN: 0027-8424
EISSN: 1091-6490
DOI: 10.1073/pnas.1606636113
PMID: 27247400
Source: GFMER Free Medical Journals
MEDLINE
PubMed Central

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

Volumes 1–89 and 106–113, copyright as a collective work only; author(s) retains copyright to individual articles ;ISSN: 0027-8424 ;EISSN: 1091-6490 ;DOI: 10.1073/pnas.1606636113 ;PMID: 27247400

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