The main aim of this project involves characterizing the role of the HIV envelope protein (gp120/41) in the pathogenesis of HIV disease. This effort has included biochemical and biological characterizations of the interaction between cell surface receptors and the HIV envelope. In addition we are studying the role of envelope-mediated signals in pathogenesis. We have identified a new interaction between gp120 and integrin alpha4beta7, which functions as the gut-homing receptor. Because the function of alpha4beta7 is intimately linked to gut associated lymphoid tissue, which is a principal site of HIV replication, we hypothesize that envelope-alpha4beta7 interactions play an important role in HIV pathogenesis. We have found that alpha4beta7high CD4+ T cells are more susceptible to productive infection by HIV than are alpha4beta7low-neg CD4+ T cells, in part because the former cellular subset is enriched with metabolically active cells. We determined that on these cells, alpha4beta7 appears in a complex with the CD4 receptor. We hypothesized that the specific affinity of gp120 for alpha4beta7 provides a mechanism for HIV to target metabolically active CD4+ T cells and that such an activity might prove critical for efficient virus propagation and dissemination following mucosal transmission. In addition we have investigated the interaction between HIV and alpha4beta7 on lymphocyte subsets other than CD4+ T cells. We have learned that some of the defects associated with HIV disease result from these interactions.

Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
2013
Total Cost
$574,419
Indirect Cost
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State
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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
Park, Chung; Arthos, James; Cicala, Claudia et al. (2015) The HIV-1 envelope protein gp120 is captured and displayed for B cell recognition by SIGN-R1(+) lymph node macrophages. Elife 4:
Kamenyeva, Olena; Boularan, Cedric; Kabat, Juraj et al. (2015) Neutrophil recruitment to lymph nodes limits local humoral response to Staphylococcus aureus. PLoS Pathog 11:e1004827
Byrareddy, Siddappa N; Sidell, Neil; Arthos, James et al. (2015) Species-specific differences in the expression and regulation of α4β7 integrin in various nonhuman primates. J Immunol 194:5968-79
Cicala, Claudia; Arthos, James (2014) Virion attachment and entry: HIV gp120 Env biotinylation, gp120 Env, or integrin ligand-binding assay. Methods Mol Biol 1087:3-12
Byrareddy, Siddappa N; Kallam, Brianne; Arthos, James et al. (2014) Targeting α4β7 integrin reduces mucosal transmission of simian immunodeficiency virus and protects gut-associated lymphoid tissue from infection. Nat Med 20:1397-400
Cimbro, Raffaello; Vassena, Lia; Arthos, James et al. (2012) IL-7 induces expression and activation of integrin α4β7 promoting naive T-cell homing to the intestinal mucosa. Blood 120:2610-9
McKinnon, Lyle R; Nyanga, Billy; Chege, Duncan et al. (2011) Characterization of a human cervical CD4+ T cell subset coexpressing multiple markers of HIV susceptibility. J Immunol 187:6032-42
Cicala, Claudia; Arthos, James; Fauci, Anthony S (2011) HIV-1 envelope, integrins and co-receptor use in mucosal transmission of HIV. J Transl Med 9 Suppl 1:S2
Zou, Zhongcheng; Chastain, Ashley; Moir, Susan et al. (2011) Siglecs facilitate HIV-1 infection of macrophages through adhesion with viral sialic acids. PLoS One 6:e24559

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