title: Cryptic determinant of α4β7 binding in the V2 loop of HIV-1 gp120.
abstract: The peptide segment of the second variable loop of HIV-1 spanning positions 166-181 harbors two functionally important sites. The first, spanning positions 179-181, engages the human α4β7 integrin receptor which is involved in T-cell gut-homing and may play a role in human immunodeficiency virus (HIV)-host cell interactions. The second, at positions 166-178, is a major target of anti-V2 antibodies elicited by the ALVAC/AIDSVAX vaccine used in the RV144 clinical trial. Notably, these two sites are directly adjacent, but do not overlap. Here, we report the identity of a second determinant of α4β7 binding located at positions 170-172 of the V2 loop. This segment - tripeptide QRV170-172- is located within the second site, yet functionally affects the first site. The absence of this segment abrogates α4β7 binding in peptides bearing the same sequence from position 173-185 as the V2 loops of the RV144 vaccines. However, peptides exhibiting V2 loop sequences from heterologous HIV-1 strains that include this QRV170-172 motif bind the α4β7 receptor on cells. Therefore, the peptide segment at positions 166-178 of the V2 loop of HIV-1 viruses appears to harbor a cryptic determinant of α4β7 binding. Prior studies show that the anti-V2 antibody response elicited by the RV144 vaccine, along with immune pressure inferred from a sieve analysis, is directed to this same region of the V2 loop. Accordingly, the anti-V2 antibodies that apparently reduced the risk of infection in the RV144 trial may have functioned by blocking α4β7-mediated HIV-host cell interactions via this cryptic determinant.
authors.affiliation: Office for Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; United States Military Health Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: Boonrat
authors.initials: B
authors.lastname: Tassaneetrithep
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Doreen
authors.initials: D
authors.lastname: Tivon
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Swetnam
authors.affiliation: Department of Retrovirology, United States Army Medical Component, Armed Forces Research Institute of Medical Sciences, Bangkok Thailand.
authors.forename: Nicos
authors.initials: N
authors.lastname: Karasavvas
authors.affiliation: United States Military Health Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: Nelson L
authors.initials: NL
authors.lastname: Michael
authors.affiliation: United States Military Health Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: Jerome H
authors.initials: JH
authors.lastname: Kim
authors.affiliation: United States Military Health Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: Mary
authors.initials: M
authors.lastname: Marovich
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Timothy
authors.initials: T
authors.lastname: Cardozo
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000595:Amino Acid Sequence; D000956:Antigens, Viral / Q000276:immunology; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015658:HIV Infections; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D016023:Integrins / Q000276:immunology*; D011485:Protein Binding; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D019562:Viral Load
chemical_list: D016915:AIDS Vaccines; C112734:AIDSVAX; D000956:Antigens, Viral; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D016023:Integrins; C514793:gp120 protein, Human immunodeficiency virus 1; C071777:integrin alpha4beta7