During the acute phase of an HIV infection, the predominant depletion of CD4+ T cells is localized to thegastrointestinal tract. Furthermore, this substantial depletion does not fully recover with highly active antiviralretroviral therapy. These observations, confirmed in the SIV model of AIDS progression in the Rhesusmacaque, indicate that the intestinal immune response is compromised early and suggest that the infectedhost may be vulnerable to microbial translocation due to (i) increased permeability in the epithelium as wellas (ii) loss of mucosal immune function. Consistent with this expectation, our recent data demonstrateincreased circulating levels of bacterial lipopolysaccharide, peptidoglycan, and DMA in plasma of HIVinfectedindividuals. A consequence of increased microbial translocation is systemic innate and adaptiveimmune activation (to be studied in Projects 1, 3, and 4), which is also incompletely reversed after successfulHAART. Therefore, we hypothesize that the chronic systemic immune activation diagnostic of AIDSprogression may, in part, be a result of increased paracellular epithelial permeability due to an earlyloss in intestinal immune defenses. In addition, we will test a secondary hypothesis that increasedmicrobial translocation is a result of a diminished or compromised humoral immune response in theintestine. Since the molecular mechanisms for increased intestinal permeability during HIV infection areunknown, we propose:
Aim 1 : Determine the location and kinetics of breach incidence in the epithelialbarrier by measuring intestinal permeability (IP) directly in HIV-infected patients and SIV-infected Rhesusmacaques or Sooty mangabeys. Gastrointestinal permeability will be assessed by measuring the movementof saccharide probes across the epithelium of the stomach, small intestine, and colon in HIV or SIVinfections.
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, andgene expression of the protein components of the AJC from the terminal ileum and colon of control and HIVorSIV-infected subjects will be compared.
Aim 3 : Delineate the innate and adaptive immunologicaldysfunctions 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 andothers, 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 PAMPconcentration in the lamina propria are reduced, after highly active antiretroviral therapy (HAART) haslessened viral replication. Since HIV DNA is found in the intestinal mucosa even after HAART, we willinvestigate the degree to which accumulated deficiencies in the epithelium are corrected by HAART.
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