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

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Abstract

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 of gp120, a peptide motif that mimics structures presented by the natural ligands of α4β7. On CD4+ T cells, engagement of α4β7 by gp120 resulted in rapid activation of LFA-1, the central integrin involved in the establishment of virological synapses, which facilitate efficient cell-to-cell spreading of HIV-1.

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Figure 1: Binding of gp120 to α4β7 on NK cells.
Figure 2: Integrin α4β7 mediates CD4-independent binding of gp120 on retinoic acid?treated T cells.
Figure 3: Binding to α4β7 uses a Leu-Asp-Val sequence in the gp120 V2 loop.
Figure 4: Sequence conservation of the α4β7-binding motif in the V2 loop of HIV-1.
Figure 5: Binding of gp120 to α4β7 activates LFA-1.
Figure 6: Integrin α4β7 localizes together with active LFA-1 and CD4 at the interface of adhesive junctions.
Figure 7: Reversion of a Leu-Asp-Val?mutant HIV-1 provirus results in enhanced sensitivity to gp120-α4β7 antagonists.

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Acknowledgements

We thank S. Shaw, G. Snyder, T.-W. Chun, A. Kinter and S. Moir for discussions; J.I. Mullins for providing the AN1 coding sequence; J. Weddle for figure preparation; and the National Institutes of Health AIDS Research and Reference Reagent Program for many reagents. Act-1 was provided by S. Shaw (National Cancer Institute), and NL43-SF162 was provided by R.L. Willey (National Institute of Allergy and Infectious Diseases). Supported by the National Institutes of Health (AI058894 and AI047734 to S.M.; and the Intramural Research Program).

Author information

D.J.G., K.M., E.M., C.C., J.M., M.P., D.W., S.K., C.C.C., N.C., E.C., K.N.R. and D.V.R. did biological experiments; Z.X., T.D.V., T.P.C. and R.A.L. did proteomic and bioinformatics analyses; J.A., C.C., E.M. and A.S.F. conceived and designed experiments; and all authors participated in manuscript preparation.

Correspondence to James Arthos.

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