The natural history of HIV-1 infection is characterized by the acquisition of viral infection across mucosal surfaces and the selective acquisition and expansion of R5 viruses, despite exposure of the recipient to a quasi species consisting of X4 and R5 viruses. To address this topic, we have developed a unique in vitro human model system for studying early virus selection and replication events at the mucosal surface of the gastrointestinal tract, a site critical for perinatal and sexual transmission of HIV-1 and presumably for successful development of HIV-1 vaccines. This grant proposes to extend our studies by defining the cellular and molecular basis for selective transmission of R5 virus across the intestinal epithelium. The central theme is the role of intestinal epithelial cells and intestinal lymphocytes in the selective transfer and early replication of a subpopulation of HIV-1 that is characterized by the use of CCR5 as a coreceptor and by shortened variable loop structure and glycosylation changes in the envelope gp120 SU domain. We propose to test the following hypotheses: (1) Intestinal epithelial cells internalize both R5 and X4 viruses from a pool of viruses inoculated onto the mucosa but selectively transport only R5 viruses by CCR5-mediated endocytic transcytosis, a process that provides intracellular protection for R5, but not X4, viruses. (2) In addition to the selective transport of R5 viruses, intestinal epithelial cells and/or intestinal lymphocytes select from a mixed virus population a subset that is characterized by shorter variable loop structures with fewer glycosylation sites in the gp120 SU domain that in turn is preferentially replicated and amplified in early HIV-1 infection. Using primary intestinal cells, we propose to test these hypotheses with three Specific Aims:(1) Define the molecular mechanism by which polarized primary intestinal epithelial cells selectively transfer R5 HIV-1 to intestinal (lamina propria) lymphocytes.(2) Elucidate whether primary intestinal epithelial cells also selectively transfer genotypically distinct R5viruses via selective internalization of viruses that have distinct glycosylation patterns in the variable loop structures of gp120. (3) Determine whether intestinal (lamina propria)lymphocytes participate in the selection of the genotypic minor variant that characterizes the transmitted virus in acutely infected recipients.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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AIDS and Related Research 8 (AARR)
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Hamilton, Frank A
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University of Alabama Birmingham
Internal Medicine/Medicine
Schools of Medicine
United States
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Smith, P D; Smythies, L E; Shen, R et al. (2011) Intestinal macrophages and response to microbial encroachment. Mucosal Immunol 4:31-42
Shen, Ruizhong; Meng, Gang; Ochsenbauer, Christina et al. (2011) Stromal down-regulation of macrophage CD4/CCR5 expression and NF-?B activation mediates HIV-1 non-permissiveness in intestinal macrophages. PLoS Pathog 7:e1002060
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Shen, Ruizhong; Drelichman, Ernesto R; Bimczok, Diane et al. (2010) GP41-specific antibody blocks cell-free HIV type 1 transcytosis through human rectal mucosa and model colonic epithelium. J Immunol 184:3648-55
Raska, Milan; Takahashi, Kazuo; Czernekova, Lydie et al. (2010) Glycosylation patterns of HIV-1 gp120 depend on the type of expressing cells and affect antibody recognition. J Biol Chem 285:20860-9
Shen, Ruizhong; Smythies, Lesley E; Clements, Ronald H et al. (2010) Dendritic cells transmit HIV-1 through human small intestinal mucosa. J Leukoc Biol 87:663-70
Smythies, Lesley E; Shen, Ruizhong; Bimczok, Diane et al. (2010) Inflammation anergy in human intestinal macrophages is due to Smad-induced IkappaBalpha expression and NF-kappaB inactivation. J Biol Chem 285:19593-604
Raska, Milan; Novak, Jan (2010) Involvement of envelope-glycoprotein glycans in HIV-1 biology and infection. Arch Immunol Ther Exp (Warsz) 58:191-208

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