Integrin α4β7 in HIV‐1 infection: A critical review

Over the past decade, a series of observations linking α4β7, the principal gut‐homing integrin, with various aspects of HIV‐1 infection have generated considerable interest in the field of HIV‐1 research. After the initial report that the major HIV‐1 envelope glycoprotein, gp120, can bind to α4β7, intensive research efforts have been focused on the role of α4β7 as a key factor in HIV‐1 pathogenesis and as a potential target for prevention and treatment. The interaction between α4β7 and its natural ligand, MAdCAM‐1, directs infected CD4+ T cells and HIV‐1 virions carrying incorporated α4β7 to the gut mucosa, which may facilitate HIV‐1 seeding and replication in the intestinal compartment during the early stages of infection. In addition, cells that express high levels of α4β7, such as Th17 cells, represent preferential targets for infection, and their frequency in the circulation was shown to correlate with susceptibility to HIV‐1 infection and disease progression. A number of in vivo studies in nonhuman primates have investigated whether blockage of α4β7 may affect SIV transmission and pathogenesis. Administration of a primatized anti‐α4β7 antibody that blocks MAdCAM‐1 binding to α4β7 was reported to reduce SIV mucosal transmission in rhesus macaques. However, the mechanism responsible for such a protective effect is still undefined, and conflicting results have been reported on the effects of the same antibody, in combination with ART, during the early chronic phase of SIV infection. Thus, despite a series of tantalizing results accrued over the past decade, the jury is still out on the role of α4β7 in HIV‐1 infection.

[1]  M. Proschan,et al.  An open-label phase 1 clinical trial of the anti-α4β7 monoclonal antibody vedolizumab in HIV-infected individuals , 2019, Science Translational Medicine.

[2]  J. Lifson,et al.  Blocking α4β7 integrin binding to SIV does not improve virologic control , 2019, Science.

[3]  K. Reimann,et al.  Lack of therapeutic efficacy of an antibody to α4β7 in SIVmac251-infected rhesus macaques , 2019, Science.

[4]  M. Proschan,et al.  Evaluation of an antibody to α4β7 in the control of SIVmac239-nef-stop infection , 2019, Science.

[5]  J. Mascola,et al.  Delayed vaginal SHIV infection in VRC01 and anti-α4β7 treated rhesus macaques , 2019, PLoS pathogens.

[6]  Kathy O. Lui,et al.  Vedolizumab-mediated integrin α4β7 blockade does not control HIV-1SF162 rebound after cART interruption in humanized mice. , 2019, AIDS.

[7]  K. To,et al.  Vedolizumab-mediated integrin α4β7 blockade does not control HIV-1SF162 rebound after combination antiretroviral therapy interruption in humanized mice. , 2019, AIDS.

[8]  H. Ueno,et al.  Anti-α4β7 therapy targets lymphoid aggregates in the gastrointestinal tract of HIV-1–infected individuals , 2018, Science Translational Medicine.

[9]  M. Soares,et al.  MAdCAM costimulation through Integrin-alpha(4)beta(7) promotes HIV replication , 2018 .

[10]  M. Soares,et al.  MAdCAM costimulation through Integrin-α4β7 promotes HIV replication , 2018, Mucosal Immunology.

[11]  A. Fauci,et al.  The Role of Integrin α4β7 in HIV Pathogenesis and Treatment , 2018, Current HIV/AIDS Reports.

[12]  A. Fauci,et al.  Signal peptide of HIV envelope protein impacts glycosylation and antigenicity of gp120 , 2018, Proceedings of the National Academy of Sciences.

[13]  R. Kaul,et al.  Integrin α4β7 expression on peripheral blood CD4+ T cells predicts HIV acquisition and disease progression outcomes , 2018, Science Translational Medicine.

[14]  A. Fauci,et al.  Virion incorporation of integrin α4β7 facilitates HIV-1 infection and intestinal homing , 2017, Science Immunology.

[15]  Jace W. Jones,et al.  Sustained virologic control in SIV+ macaques after antiretroviral and alpha(4)beta(7) antibody therapy , 2017 .

[16]  Jace W. Jones,et al.  Sustained virologic control in SIV+ macaques after antiretroviral and α4β7 antibody therapy , 2016, Science.

[17]  R. Kaul,et al.  Identification of preferential CD4+ T-cell targets for HIV infection in the cervix , 2015, Mucosal Immunology.

[18]  S. Karim,et al.  South African HIV-1 subtype C transmitted variants with a specific V2 motif show higher dependence on α4β7 for replication , 2015, Retrovirology.

[19]  A. Gettie,et al.  Retinoic Acid Imprints a Mucosal-like Phenotype on Dendritic Cells with an Increased Ability To Fuel HIV-1 Infection , 2015, The Journal of Immunology.

[20]  M. Brameier,et al.  Targeting α4β7 integrin reduces mucosal transmission of SIV and protects GALT from infection , 2014, Nature Medicine.

[21]  Hua-Xin Liao,et al.  Envelope Glycoprotein Binding to the Integrin α4β7 Is Not a General Property of Most HIV-1 Strains , 2014, Journal of Virology.

[22]  M. Lederman,et al.  IL-7 induces expression and activation of integrin α4β7 promoting naive T-cell homing to the intestinal mucosa. , 2012, Blood.

[23]  H. Ding,et al.  Transmitted/Founder and Chronic Subtype C HIV-1 Use CD4 and CCR5 Receptors with Equal Efficiency and Are Not Inhibited by Blocking the Integrin α4β7 , 2012, PLoS pathogens.

[24]  A. Fauci,et al.  The Genotype of Early-Transmitting HIV gp120s Promotes α4β7 –Reactivity, Revealing α4β7 +/CD4+ T cells As Key Targets in Mucosal Transmission , 2011, PLoS pathogens.

[25]  K. Reimann,et al.  Blocking of α4β7 Gut-Homing Integrin during Acute Infection Leads to Decreased Plasma and Gastrointestinal Tissue Viral Loads in Simian Immunodeficiency Virus-Infected Rhesus Macaques , 2011, The Journal of Immunology.

[26]  R. Kaul,et al.  The integrin α4β7 forms a complex with cell-surface CD4 and defines a T-cell subset that is highly susceptible to infection by HIV-1 , 2009, Proceedings of the National Academy of Sciences.

[27]  J. Lifson,et al.  α4+β7hiCD4+ memory T cells harbor most Th-17 cells and are preferentially infected during acute SIV infection , 2009, Mucosal Immunology.

[28]  Carole R. Baskin,et al.  Critical Loss of the Balance between Th17 and T Regulatory Cell Populations in Pathogenic SIV Infection , 2009, PLoS pathogens.

[29]  D. Douek,et al.  Differential Th17 CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections. , 2008, Blood.

[30]  Eva Chung,et al.  HIV-1 envelope protein binds to and signals through integrin α4β7, the gut mucosal homing receptor for peripheral T cells , 2008, Nature Immunology.

[31]  M. Markowitz,et al.  Lack of Mucosal Immune Reconstitution during Prolonged Treatment of Acute and Early HIV-1 Infection , 2006, PLoS medicine.

[32]  Christine Hogan,et al.  Primary HIV-1 Infection Is Associated with Preferential Depletion of CD4+ T Lymphocytes from Effector Sites in the Gastrointestinal Tract , 2004, The Journal of experimental medicine.

[33]  J. Flamm,et al.  Severe CD4+ T-Cell Depletion in Gut Lymphoid Tissue during Primary Human Immunodeficiency Virus Type 1 Infection and Substantial Delay in Restoration following Highly Active Antiretroviral Therapy , 2003, Journal of Virology.

[34]  C. Melief,et al.  Antigen-Antibody Immune Complexes Empower Dendritic Cells to Efficiently Prime Specific CD8+ CTL Responses In Vivo1 , 2002, The Journal of Immunology.

[35]  Roberts Bd,et al.  Host protein incorporation is conserved among diverse HIV-1 subtypes. , 1999 .

[36]  M. Zeitz,et al.  HIV/SIV Enteropathy , 1998, Annals of the New York Academy of Sciences.

[37]  M. Tremblay,et al.  The acquisition of host-encoded proteins by nascent HIV-1. , 1998, Immunology today.

[38]  R P Johnson,et al.  Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. , 1998, Science.

[39]  D. Ott Cellular proteins in HIV virions , 1997, Reviews in medical virology.

[40]  C. Mackay,et al.  Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue. , 1997, The American journal of pathology.

[41]  坪田 一男 Keystone symposia , 1996, Current Biology.

[42]  E. Berg,et al.  α4β7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1 , 1993, Cell.

[43]  Y. Tanaka,et al.  Selective expression of integrin alpha 4 beta 7 on a subset of human CD4+ memory T cells with Hallmarks of gut-trophism. , 1993, Journal of immunology.

[44]  S. Dandekar,et al.  Simian immunodeficiency virus infection of the gastrointestinal tract of rhesus macaques. Functional, pathological, and morphological changes. , 1993, The American journal of pathology.

[45]  A. Lackner,et al.  Distribution of SIV infection in the gastrointestinal tract of rhesus macaques at early and terminal stages of AIDS. , 1993, Journal of medical primatology.

[46]  R. Kaul,et al.  Integrin alpha(4)beta(7) expression on peripheral blood CD4(+) T cells predicts HIV acquisition and disease progression outcomes , 2022 .

[47]  Paul,et al.  Targeting alpha(4)beta(7) integrin reduces mucosal transmission of simian immunodeficiency virus and protects gut-associated lymphoid tissue from infection , 2022 .