During the acute phase of an HIV infection, the predominant depletion of CD4+ T cells is localized to the gastrointestinal tract. Furthermore, this substantial depletion does not fully recover with highly active antiviral retroviral therapy. These observations, confirmed in the SIV model of AIDS progression in the Rhesus macaque, indicate that the intestinal immune response is compromised early and suggest that the infected host may be vulnerable to microbial translocation due to (i) increased permeability in the epithelium as well as (ii) loss of mucosal immune function. Consistent with this expectation, our recent data demonstrate increased circulating levels of bacterial lipopolysaccharide, peptidoglycan, and DMA in plasma of HIVinfected individuals. A consequence of increased microbial translocation is systemic innate and adaptive immune activation (to be studied in Projects 1, 3, and 4), which is also incompletely reversed after successful HAART. Therefore, we hypothesize that the chronic systemic immune activation diagnostic of AIDS progression may, in part, be a result of increased paracellular epithelial permeability due to an early loss in intestinal immune defenses. In addition, we will test a secondary hypothesis that increased microbial translocation is a result of a diminished or compromised humoral immune response in the intestine. Since the molecular mechanisms for increased intestinal permeability during HIV infection are unknown, we propose:
Aim 1 : Determine the location and kinetics of breach incidence in the epithelial barrier by measuring intestinal permeability (IP) directly in HIV-infected patients and SIV-infected Rhesus macaques or Sooty mangabeys. Gastrointestinal permeability will be assessed by measuring the movement of saccharide probes across the epithelium of the stomach, small intestine, and colon in HIV or SIV infections.
Aim 2 : Evaluate the biochemical and structural integrity of the epithelial apical junctional complex (AJC) in acute and chronic HIV and SIV infection. The composition, assembly, intracellular trafficking, and gene expression of the protein components of the AJC from the terminal ileum and colon of control and HIVor SIV-infected subjects will be compared.
Aim 3 : Delineate the innate and adaptive immunological dysfunctions in the HIV-infected mucosa that contribute to and are a consequence of microbial translocation. Intestinal biopsies of HIV- or SIV-infected subjects will be probed for the presence of bacterial DNA and others, PAMPs, and for evidence of ongoing toll-like receptor signal transduction, and IgA deficiency.
Aim 4 : Investigate the degree to which intestinal permeability, apical junctional complex integrity, and PAMP concentration in the lamina propria are reduced, after highly active antiretroviral therapy (HAART) has lessened viral replication. Since HIV DNA is found in the intestinal mucosa even after HAART, we will investigate the degree to which accumulated deficiencies in the epithelium are corrected by HAART.
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