HIV-1 envelope protein binds to and signals through integrin α4β7, the gut mucosal homing receptor for peripheral T cells

  title={HIV-1 envelope protein binds to and signals through integrin $\alpha$4$\beta$7, the gut mucosal homing receptor for peripheral T cells},
  author={James Arthos and Claudia Cicala and Elena Martinelli and Katilyn Macleod and Donald Van Ryk and Danlan Wei and Zhen Xiao and Timothy D. Veenstra and Thomas P. Conrad and Richard A. Lempicki and Sherry McLaughlin and Massimiliano Pascuccio and Ravindra Gopaul and Jonathan P. McNally and Catherine C Cruz and Nina M Censoplano and Eva Chung and Kristin N. Reitano and Shyam Kottilil and Diana J. Goode and Anthony S. Fauci},
  journal={Nature Immunology},
Infection with human immunodeficiency virus 1 (HIV-1) results in the dissemination of virus to gut-associated lymphoid tissue. Subsequently, HIV-1 mediates massive depletion of gut CD4+ T cells, which contributes to HIV-1-induced immune dysfunction. The migration of lymphocytes to gut-associated lymphoid tissue is mediated by integrin α4β7. We demonstrate here that the HIV-1 envelope protein gp120 bound to an activated form of α4β7. This interaction was mediated by a tripeptide in the V2 loop… 

Distinct chemokines selectively induce HIV-1 gp120-integrin α4β7 binding via triggering conformer-specific activation of α4β7

The findings demonstrate that gp120-α4β7 interaction has an important role in HIV infection and indicate that the ligand binding to integrin α4 β7 is dependent on the distinct integrin active conformations induced by different chemokines.

Antibody against integrin lymphocyte function-associated antigen 1 inhibits HIV type 1 infection in primary cells through caspase-8-mediated apoptosis.

It is demonstrated that inhibition of the LFA-1/ICAM-1 interaction by a monoclonal antibody leads to decreased virus production and spread in association with increased apoptosis of HIV-infected primary T cells.

HIV-1 gp120 impairs B cell proliferation by inducing TGF-β1 production and FcRL4 expression

The studies identify a mechanism whereby the virus may subvert the early HIV-1-specific humoral immune response and indicate that in addition to mediating chronic activation of the immune system, viral proteins contributed directly to HIV- 1-associated B cell dysfunction.

Envelope Glycoprotein Binding to the Integrin α4β7 Is Not a General Property of Most HIV-1 Strains

Evidence indicates that infectious HIV-1 virions and many gp120s lack detectable α4β7 binding activity, suggesting that this homing receptor may play a limited role in direct HIV- 1 infection of cells.

Binding of HIV-1 virions to α4β7 expressing cells and impact of antagonizing α4β7 on HIV-1 infection of primary CD4+ T cells

The findings indicate that α4β7 may serve as an attachment factor at least for some HIV-1 strains, and provides a promising means for the investigation of other viral strains to understand the potential roles of α4 β7 in HIV- 1 infection.

The Role of Integrin α4β7 Signaling in Human Immunodeficiency Virus-1 Pathogenesis and Viral Entry in Primary CD4+ T Cells As Revealed by Comparative Phosphoproteomic Signatures.

This report determined phosphoproteomic signatures of HIV-1 gp120 signaling as well as signaling mediated by the integrin α4β7 ligand, mucosal vascular addressin cell adhesion molecule-1 (MAdCAM-1), in primary CD4+ T cells and identified proteins associated with both classical and nonclassical integrin functions.

Cell adhesion through alphaV-containing integrins is required for efficient HIV-1 infection in macrophages.

It is shown that inhibition of alphaV integrin in monocyte-derived macrophages, by RNA interference or their inhibition by a selective small heterocyclic RGD-mimetic nonpeptide compound, inhibited the replication of HIV in the absence of cytotoxicity.

HIV-1 envelope gp 120-induced partial T-cell receptor signaling creates an F-1 actin-depleted zone in the virological synapse 2 3

A model in which the F-actin depleted zone formed within the target CD4 T cell enhances the reception of virions by releasing the physical barrier for HIV-1 entry and facilitating post-entry events is proposed.

Human Immunodeficiency Virus Type 1 Envelope gp120-Induced Partial T-Cell Receptor Signaling Creates an F-Actin-Depleted Zone in the Virological Synapse

A model in which the F-actin-depleted zone formed within the target CD4 T cell enhances the reception of virions by releasing the physical barrier for HIV-1 entry and facilitating postentry events is proposed.

Integrin α4β7 Is Downregulated on the Surfaces of Simian Immunodeficiency Virus SIVmac239-Infected Cells

Downregulation of integrin α4β7 may have an unappreciated role in the CD4 depletion of the mucosal-associated lymphoid compartments, susceptibility to superinfection, and/or immune evasion.



HIV-1 Cell to Cell Transfer across an Env-induced, Actin-dependent Synapse

It is proposed that receptor engagement by Env directs the rapid, actin-dependent recruitment of HIV receptors and adhesion molecules to the interface, resulting in a stable adhesive junction across which HIV infects the target cell.

T Cells Expressing Activated LFA-1 Are More Susceptible to Infection with Human Immunodeficiency Virus Type 1 Particles Bearing Host-Encoded ICAM-1

It is shown here that conversion of LFA-1 to high affinity for ICAM-1 with the use of anti-L FA-1 antibodies markedly enhances the susceptibility of different target T-lymphoid cell lines, as well as of primary peripheral blood mononuclear cells, to infection by ICam-1-bearing HIV-1 particles.

Regulation of LFA-1 Activity through Cytoskeleton Remodeling and Signaling Components Modulates the Efficiency of HIV Type-1 Entry in Activated CD4+ T Lymphocytes1

It is demonstrated in this study that activation of primary human CD4+ T lymphocytes increases L FA-1 affinity and avidity states, two events promoting the early events of the HIV-1 replication cycle through interactions between virus-embedded host ICAM-1 and LFA-1 clusters.

Macrophage-tropic HIV and SIV envelope proteins induce a signal through the CCR5 chemokine receptor

It is shown that recombinant envelope proteins from macrophage-tropic HIV and SIV induce a signal through CCR5 on CD4+ T cells and that envelope-mediated signal transduction through C CR5 induces chemotaxis of T cells.

LFA-1 Is a Key Determinant for Preferential Infection of Memory CD4+ T Cells by Human Immunodeficiency Virus Type 1

Light is shed on a potential mechanism by which HIV-1 preferentially targets long-lived memory CD4+ T cells, as exemplified by a more important virus replication, an increase in integrated viral DNA copies, and a more efficient entry process.

Induction of phosphorylation and intracellular association of CC chemokine receptor 5 and focal adhesion kinase in primary human CD4+ T cells by macrophage-tropic HIV envelope.

It is demonstrated here that a recombinant envelope protein derived from an M-tropic isolate of HIV-1 can transduce CD4-dependent as well as CCR5-dependent intracellular signals in primary human CD4+ T cells.

Structural definition of a conserved neutralization epitope on HIV-1 gp120

A site of vulnerability, related to a functional requirement for efficient association with CD4, can therefore be targeted by antibody to neutralize HIV-1.

Innate Immune Dysfunction in HIV Infection: Effect of HIV Envelope-NK Cell Interactions12

Data demonstrate that exposure of NK cells to HIV envelope proteins results in profound cellular abnormalities at the level of gene expression as well as generic cell functions, likely to be a consequence of a direct HIV gp120-mediated effect on NK cells.

HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites

It is shown that recognition by receptor-binding-site antibodies induces conformational change, and conformational masking enables HIV-1 to maintain receptor binding and simultaneously to resist neutralization.

Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells

It is shown that peak virus production in gut tissues of SIV-infected rhesus macaques coincides with peak numbers of infected memory CD4+ T cells, underscoring the importance of developing countermeasures to SIV that are effective before infection of GALT.