This project evolved from the initial observation of a direct interaction between the gut mucosal homing receptor, integrin alpha4beta7 and the HIV envelope protein gp120. This observation raised new questions related to gp120-mediated signal transduction. HIV and SIV are gut tropic viruses and alpha4beta7-gp120 interactions may shed light on the manner in which HIV impacts the function of immune cells associated with the mucosal immune system. We tested this hypothesis in a NHP model of HIV/SIV infection, and determined that an antibody specific for alpha4beta7 prevented mucosal transmission. We then demonstrated that MAdCAM, the natural ligand of alpha4beta7 delivers a potent costimulatory signal to naive and memory CD4+ T cells following ligation with alpha4beta7. Such costimulation promotes high levels of HIV replication. The anti- alpha4beta7 mAb, that prevented mucosal transmission of SIV, blocks MAdCAM signaling through alpha4beta7 and MAdCAM-dependent viral replication. Subsequently, we demonstrated that the specific affinity of alpha4beta7 for gp120 is similar to its affinity for MAdCAM. We have recently reported that alpha4beta7 binding maps to the V2 loop domain of HIV/SIV gp120. The V2 loop mimics MAdCAM in the way that it binds to alpha4beta7. This mimicry of MAdCAM- a4b7 interactions by V2 may influence early events in HIV infection, particularly the rapid seeding of gut tissues, and supports the view that HIV replication in gut tissue is a central feature of HIV pathogenesis.

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19
Fiscal Year
2019
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Santangelo, P J; Cicala, C; Byrareddy, S N et al. (2018) Early treatment of SIV+ macaques with an ?4?7 mAb alters virus distribution and preserves CD4+ T cells in later stages of infection. Mucosal Immunol 11:932-946
Calenda, Giulia; Keawvichit, Rassamon; Arrode-Brusés, Géraldine et al. (2018) Integrin ?4?7 Blockade Preferentially Impacts CCR6+ Lymphocyte Subsets in Blood and Mucosal Tissues of Naive Rhesus Macaques. J Immunol 200:810-820
Nawaz, Fatima; Goes, Livia R; Ray, Jocelyn C et al. (2018) MAdCAM costimulation through Integrin-?4?7 promotes HIV replication. Mucosal Immunol 11:1342-1351
Yolitz, Jason; Schwing, Catherine; Chang, Julia et al. (2018) Signal peptide of HIV envelope protein impacts glycosylation and antigenicity of gp120. Proc Natl Acad Sci U S A 115:2443-2448
Arthos, James; Cicala, Claudia; Nawaz, Fatima et al. (2018) The Role of Integrin ?4?7 in HIV Pathogenesis and Treatment. Curr HIV/AIDS Rep 15:127-135
Sivro, Aida; Schuetz, Alexandra; Sheward, Daniel et al. (2018) Integrin ?4?7 expression on peripheral blood CD4+ T cells predicts HIV acquisition and disease progression outcomes. Sci Transl Med 10:
Kijak, Gustavo H; Sanders-Buell, Eric; Chenine, Agnes-Laurence et al. (2017) Rare HIV-1 transmitted/founder lineages identified by deep viral sequencing contribute to rapid shifts in dominant quasispecies during acute and early infection. PLoS Pathog 13:e1006510
Kijak, Gustavo H; Sanders-Buell, Eric; Chenine, Agnes-Laurence et al. (2017) Correction: Rare HIV-1 transmitted/founder lineages identified by deep viral sequencing contribute to rapid shifts in dominant quasispecies during acute and early infection. PLoS Pathog 13:e1006620
Girard, Alexandre; Jelicic, Katija; Van Ryk, Don et al. (2017) Neutralizing and Targeting Properties of a New Set of ?4?7-Specific Antibodies Are Influenced by Their Isotype. J Acquir Immune Defic Syndr 75:118-127
Cicala, Claudia; Nawaz, Fatima; Jelicic, Katija et al. (2016) HIV-1 gp120: A Target for Therapeutics and Vaccine Design. Curr Drug Targets 17:122-35

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