title: Influence of the Envelope gp120 Phe 43 Cavity on HIV-1 Sensitivity to Antibody-Dependent Cell-Mediated Cytotoxicity Responses.
abstract: HIV-1-infected cells presenting envelope glycoproteins (Env) in the CD4-bound conformation on their surface are preferentially targeted by antibody-dependent cellular-mediated cytotoxicity (ADCC). HIV-1 has evolved sophisticated mechanisms to avoid the exposure of Env ADCC epitopes by downregulating CD4 and by limiting the overall amount of Env on the cell surface. In HIV-1, substitution of large residues such as histidine or tryptophan for serine 375 (S375H/W) in the gp120 Phe 43 cavity, where Phe 43 of CD4 contacts gp120, results in the spontaneous sampling of an Env conformation closer to the CD4-bound state. While residue S375 is well conserved in the majority of group M HIV-1 isolates, CRF01_AE strains have a naturally occurring histidine at this position (H375). Interestingly, CRF01_AE is the predominant circulating strain in Thailand, where the RV144 trial took place. In this trial, which resulted in a modest degree of protection, ADCC responses were identified as being part of the correlate of protection. Here we investigate the influence of the Phe 43 cavity on ADCC responses. Filling this cavity with a histidine or tryptophan residue in Env with a natural serine residue at this position (S375H/W) increased the susceptibility of HIV-1-infected cells to ADCC. Conversely, the replacement of His 375 by a serine residue (H375S) within HIV-1 CRF01_AE decreased the efficiency of the ADCC response. Our results raise the intriguing possibility that the presence of His 375 in the circulating strain where the RV144 trial was held contributed to the observed vaccine efficacy.IMPORTANCEHIV-1-infected cells presenting Env in the CD4-bound conformation on their surface are preferentially targeted by ADCC mediated by HIV-positive (HIV+) sera. Here we show that the gp120 Phe 43 cavity modulates the propensity of Env to sample this conformation and therefore affects the susceptibility of infected cells to ADCC. CRF01_AE HIV-1 strains have an unusual Phe 43 cavity-filling His 375 residue, which increases the propensity of Env to sample the CD4-bound conformation, thereby increasing susceptibility to ADCC.
authors.affiliation: Centre de Recherche du CHUM, Montreal, QC, Canada.|Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC, Canada.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Prévost
authors.affiliation: Centre de Recherche du CHUM, Montreal, QC, Canada.|Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC, Canada.
authors.forename: Daria
authors.initials: D
authors.lastname: Zoubchenok
authors.affiliation: Centre de Recherche du CHUM, Montreal, QC, Canada.|Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC, Canada.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Richard
authors.affiliation: Centre de Recherche du CHUM, Montreal, QC, Canada.|Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC, Canada.
authors.forename: Maxime
authors.initials: M
authors.lastname: Veillette
authors.affiliation: Centre de Recherche du CHUM, Montreal, QC, Canada.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Pacheco
authors.affiliation: Centre de Recherche du CHUM, Montreal, QC, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Coutu
authors.affiliation: Centre de Recherche du CHUM, Montreal, QC, Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Brassard
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Parsons
authors.affiliation: HIVNAT, Thai Red Cross AIDS Research Center, Bangkok, Thailand.|Allergy and Clinical Immunology Division, Department of Medicine, Chula Vaccine Research Center, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
authors.forename: Kiat
authors.initials: K
authors.lastname: Ruxrungtham
authors.affiliation: HIVNAT, Thai Red Cross AIDS Research Center, Bangkok, Thailand.
authors.forename: Torsak
authors.initials: T
authors.lastname: Bunupuradah
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.|Henry M. Jackson Foundation for the Advancement of the Military Medicine, Bethesda, Maryland, USA.
authors.forename: Sodsai
authors.initials: S
authors.lastname: Tovanabutra
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.|Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Kwan-Ki
authors.initials: KK
authors.lastname: Hwang
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.|Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: M Anthony
authors.initials: MA
authors.lastname: Moody
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Mattia
authors.initials: M
authors.lastname: Bonsignori
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, and Department of Microbiology and Immunobiology, Division of AIDS, Harvard Medical School, Boston, Massachusetts, USA.|Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Sodroski
authors.affiliation: Centre de Recherche du CHUM, Montreal, QC, Canada.|Department of Medicine, Université de Montréal, Montreal, QC, Canada.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Kaufmann
authors.affiliation: Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: George M
authors.initials: GM
authors.lastname: Shaw
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.|Henry M. Jackson Foundation for the Advancement of the Military Medicine, Bethesda, Maryland, USA.
authors.forename: Agnès L
authors.initials: AL
authors.lastname: Chenine
authors.affiliation: Centre de Recherche du CHUM, Montreal, QC, Canada andres.finzi@umontreal.ca.|Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC, Canada.|Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada.
authors.forename: Andrés
authors.initials: A
authors.lastname: Finzi
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000920:Antibody-Dependent Cell Cytotoxicity; D001665:Binding Sites; D016384:Consensus Sequence; D057809:HEK293 Cells; D015483:HIV Antibodies / Q000502:physiology*; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology* / Q000517:prevention & control / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D011485:Protein Binding
chemical_list: D016915:AIDS Vaccines; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; C514793:gp120 protein, Human immunodeficiency virus 1
keywords: ADCC; Env; HIV-1; Phe 43 cavity; RV144; gp120