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VIRION INCORPORATION OF INTEGRIN α4β7: IMPLICATIONS FOR HIV-1 PATHOGENESIS
Christina Guzzo1, David Ichikawa1, Chung Park1, Cathy Rehm1, Claudia Cicala1, James Arthos1, Anthony S. Fauci1, John Kehrl1, Paolo Lusso1
1NIAID, Bethesda, MD, USA
The intestinal mucosa is a key anatomical site for HIV-1 replication and CD4+ T-cell depletion. Accordingly, a series of in vivo studies in macaques showed that antibody-mediated blockade of the principal gut-homing integrin, α4β7, resulted in reduced SIV transmission, delayed disease progression, and effective virus control persisting for months after antibody withdrawal. We aimed at elucidating the potential mechanism(s) underlying the protective effects of anti-α4β7 antibody treatment.
HIV-1 strains were grown in human PBMC activated in the presence/absence of retinoic acid; virion-capture assays were performed using magnetic beads armed with antibodies to α4β7 or other cellular receptors, or recombinant MAdCAM-1 or ICAM-1; α4β7+ or – viral particles were produced by co-transfection of 293T cells with HIV-1 clones with or without α4 and β7; for virion-homing studies, fluorescent α4β7+ or – virus was injected into the tail vein of C57BL/6 mice, and tissues were harvested after 30 min.
We found that integrin α4β7 is incorporated with remarkably high efficiency into the envelope of mature HIV-1 particles. Virion-incorporated α4β7 is functionally active as it binds the specific integrin ligand, MAdCAM-1, promoting HIV-1 capture by and infection of MAdCAM-expressing cells, which in turn mediates trans-infection of bystander susceptible cells. In vivo homing experiments in mice documented a selective and specific uptake of α4β7+, but not α4β7- HIV-1 virions by high endothelial venules in the Peyer's patches of the intestinal mucosa. The physiological relevance of α4β7 incorporation was corroborated by the observation that circulating virions from both HIV-infected patients and SIV-infected macaques invariably carry functional α4β7 in their envelope, with peak incorporation levels occurring during the early stages of infection, when the intestinal mucosa is still richly populated with α4β7-high CD4+ T cells.
Our results provide new insights to interpret the protective effects of anti-α4β7 antibody treatment and may be relevant for the pathogenesis, therapy and prevention of HIV-1 infection.