title: Identification of New Regions in HIV-1 gp120 Variable 2 and 3 Loops that Bind to α4β7 Integrin Receptor.
abstract: BACKGROUND
  The gut mucosal homing integrin receptor α4β7 present on activated CD4+ T cells interacts with the HIV-1 gp120 second variable loop (V2). Case control analysis of the RV144 phase III vaccine trial demonstrated that plasma IgG binding antibodies specific to scaffolded proteins expressing the first and second variable regions (V1V2) of HIV envelope protein gp120 containing the α4β7 binding motif correlated inversely with risk of infection. Subsequently antibodies to the V3 region were also shown to correlate with protection. The integrin receptor α4β7 was shown to interact with the LDI/V motif on V2 loop but recent studies suggest that additional regions of V2 loop could interact with the α4β7. Thus, there may be several regions on the V2 and possibly V3 loops that may be involved in this binding. Using a cell line, that constitutively expressed α4β7 receptors but lacked CD4, we examined the contribution of V2 and V3 loops and the ability of V2 peptide-, V2 integrin-, V3-specific monoclonal antibodies (mAbs), and purified IgG from RV144 vaccinees to block the V2/V3-α4β7 interaction.
  
  
  RESULTS
  We demonstrate that α4β7 on RPMI8866 cells bound specifically to its natural ligand mucosal addressin cell adhesion molecule-1 (MAdCAM-1) as well as to cyclic-V2 and cyclic-V3 peptides. This binding was inhibited by anti-α4β7-specific monoclonal antibody (mAb) ACT-1, mAbs specific to either V2 or V3 loops, and by purified primary virions or infectious molecular clones expressing envelopes from acute or chronic subtypes A, C, and CRF01_AE viruses. Plasma from HIV-1 infected Thai individuals as well as purified IgG from uninfected RV144 vaccinees inhibited (0-50%) the binding of V2 and V3 peptides to α4β7.
  
  
  CONCLUSIONS
  Our results indicate that in addition to the tripeptide LDI/V motif, other regions of the V2 and V3 loops of gp120 were involved in binding to α4β7 receptors and this interaction was blocked by anti-V2 peptide, anti-V2 integrin, and anti-V3 antibodies. The ability of purified IgG from some of the uninfected RV144 vaccinees to inhibit α4β7 raises the hypothesis that anti-V2 and anti-V3 antibodies may play a role in blocking the gp120-α4β7 interaction after vaccination and thus prevent HIV-1 acquisition.
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States of America.|Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, United States of America.
authors.forename: Kristina K
authors.initials: KK
authors.lastname: Peachman
authors.affiliation: 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: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States of America.|Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, United States of America.
authors.forename: Agnes-Laurence
authors.initials: AL
authors.lastname: Chenine
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States of America.|Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: McLinden
authors.affiliation: Ministry of Public Health, Bangkok, Thailand.
authors.forename: Supachai
authors.initials: S
authors.lastname: Rerks-Ngarm
authors.affiliation: Data Management Unit, Mahidol University, Bangkok, Thailand.
authors.forename: Kaewkungwal
authors.initials: K
authors.lastname: Jaranit
authors.affiliation: Royal Thai Army, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
authors.forename: Sorachai
authors.initials: S
authors.lastname: Nitayaphan
authors.affiliation: Vaccine Trials Center, Mahidol University, Bangkok, Thailand.
authors.forename: Punnee
authors.initials: P
authors.lastname: Pitisuttithum
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States of America.|Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, United States of America.
authors.forename: Sodsai
authors.initials: S
authors.lastname: Tovanabutra
authors.affiliation: Veterans Administration New York Harbor Health Care System and NYU School of Medicine, New York, United States of America.
authors.forename: Susan
authors.initials: S
authors.lastname: Zolla-Pazner
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States of America.
authors.forename: Nelson L
authors.initials: NL
authors.lastname: Michael
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States of America.
authors.forename: Jerome H
authors.initials: JH
authors.lastname: Kim
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States of America.
authors.forename: Carl R
authors.initials: CR
authors.lastname: Alving
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States of America.
authors.forename: Mangala
authors.initials: M
authors.lastname: Rao
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016022:Case-Control Studies; D002460:Cell Line; D015483:HIV Antibodies / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000276:immunology / Q000378:metabolism*; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism*; D015497:HIV-1 / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D016023:Integrins / Q000276:immunology / Q000378:metabolism*; D008969:Molecular Sequence Data; D009500:Neutralization Tests / Q000379:methods; D011485:Protein Binding / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D007074:Immunoglobulin G; D016023:Integrins; C071777:integrin alpha4beta7