title: Envelope residue 375 substitutions in simian-human immunodeficiency viruses enhance CD4 binding and replication in rhesus macaques.
abstract: 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.
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Shuyi
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Rui
authors.initials: R
authors.lastname: Kong
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Wenge
authors.initials: W
authors.lastname: Ding
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Fang-Hua
authors.initials: FH
authors.lastname: Lee
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Zahra
authors.initials: Z
authors.lastname: Parker
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Eunlim
authors.initials: E
authors.lastname: Kim
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Gerald H
authors.initials: GH
authors.lastname: Learn
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Paul
authors.initials: P
authors.lastname: Hahn
authors.affiliation: Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA 15261;
authors.forename: Ben
authors.initials: B
authors.lastname: Policicchio
authors.affiliation: Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA 15261;
authors.forename: Egidio
authors.initials: E
authors.lastname: Brocca-Cofano
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research Inc., Frederick National Laboratory, Frederick, MD 21702;
authors.forename: Claire
authors.initials: C
authors.lastname: Deleage
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research Inc., Frederick National Laboratory, Frederick, MD 21702;
authors.forename: Xingpei
authors.initials: X
authors.lastname: Hao
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Gwo-Yu
authors.initials: GY
authors.lastname: Chuang
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Jason
authors.initials: J
authors.lastname: Gorman
authors.affiliation: Department of Infectious Disease, Scripps Research Institute, Jupiter, FL 33458;
authors.forename: Matthew
authors.initials: M
authors.lastname: Gardner
authors.affiliation: Bioqual, Inc., Rockville, MD 20852;
authors.forename: Mark G
authors.initials: MG
authors.lastname: Lewis
authors.affiliation: Aaron Diamond AIDS Research Center, Rockefeller University, New York, NY 10016;
authors.forename: Theodora
authors.initials: T
authors.lastname: Hatziioannou
authors.affiliation: Center of Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215;
authors.forename: Sampa
authors.initials: S
authors.lastname: Santra
authors.affiliation: Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA 15261;
authors.forename: Cristian
authors.initials: C
authors.lastname: Apetrei
authors.affiliation: Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA 15261;
authors.forename: Ivona
authors.initials: I
authors.lastname: Pandrea
authors.affiliation: Department of Medicine, Duke University, Durham, NC 27710;
authors.forename: S Munir
authors.initials: SM
authors.lastname: Alam
authors.affiliation: Department of Medicine, Duke University, Durham, NC 27710;
authors.forename: Hua-Xin
authors.initials: HX
authors.lastname: Liao
authors.affiliation: Department of Medicine, Duke University, Durham, NC 27710;
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Medicine, Duke University, Durham, NC 27710;
authors.forename: Georgia D
authors.initials: GD
authors.lastname: Tomaras
authors.affiliation: Department of Infectious Disease, Scripps Research Institute, Jupiter, FL 33458;
authors.forename: Michael
authors.initials: M
authors.lastname: Farzan
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research Inc., Frederick National Laboratory, Frederick, MD 21702;
authors.forename: Elena
authors.initials: E
authors.lastname: Chertova
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research Inc., Frederick National Laboratory, Frederick, MD 21702;
authors.forename: Brandon F
authors.initials: BF
authors.lastname: Keele
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research Inc., Frederick National Laboratory, Frederick, MD 21702;
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Estes
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research Inc., Frederick National Laboratory, Frederick, MD 21702;
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lifson
authors.affiliation: Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, PA 19104;
authors.forename: Robert W
authors.initials: RW
authors.lastname: Doms
authors.affiliation: Department of Medicine, Duke University, Durham, NC 27710;
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.affiliation: Department of Medicine, Duke University, Durham, NC 27710;
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Sodroski
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research Inc., Frederick National Laboratory, Frederick, MD 21702;
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104; bhahn@upenn.edu shawg@upenn.edu.
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104; bhahn@upenn.edu shawg@upenn.edu.
authors.forename: George M
authors.initials: GM
authors.lastname: Shaw
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism*; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008253:Macaca mulatta; D020125:Mutation, Missense; D016097:Simian Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000378:metabolism; D015302:Simian Immunodeficiency Virus / Q000502:physiology*; D014779:Virus Replication / Q000235:genetics*; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism
chemical_list: D015704:CD4 Antigens; D054299:env Gene Products, Human Immunodeficiency Virus
keywords: CD4; HIV-1 envelope; HIV/AIDS; SHIV