PATHOGENESIS OF INTESTINAL DYSFUNCTION IN SIMIAN AIDS

Project: Research project

Project Details

Description

Intestinal malabsorption, diarrhea, and wasting are frequent manifestations
of HIV infection and may occur in early stages of disease in the absence of
other enteric pathogens. However, mechanisms by which HIV affects
intestinal mucosal morphology and function are not known. Our results
suggest that SIV-infected rhesus macaques provide an excellent animal model
to study AIDS-associated gastroenteropathy. Jejunal tissues from SIV-
infected animals had depressed digestive enzyme activities and morphometric
analysis showed crypt hyperplasia and increased mitoses suggesting a
maturational defect in proliferating epithelial cells. The main objective
of the present proposal is to elucidate the sequence of events leading to
intestinal malabsorption in SIV-infected rhesus macaques in vivo, in a
longitudinal study and to determine the effect of jejunal SIV infection on
morphology and function. An effort will be made to determine whether these
changes are a result of the direct SIV infection of the absorbing
enterocytes or are mediated by cytokines secreted by SIV-infected
inflammatory cells. SIV-infected animals will be followed for the development of malabsorption
from initial viral exposure to the terminal stages of simian AIDS using D-
xylose and fat absorption tests. Sequential jejunal biopsies, necropsy
tissues and blood samples will be obtained from these animals. The
dissemination of viral infection in intestinal mucosa will be determined
and correlated with malabsorption, epithelial cell maturation and digestive
enzyme activities. Statistical correlations will establish the
relationship among mucosal infection, altered cell proliferation and
morphology, and functional abnormalities. The level of cytokine expression
will be determined in SIV-infected jejunal mucosa to determine whether
cytokines are associated with pathogenesis. Jejunal explant cultures will
be treated with recombinant cytokines and analyzed for epithelial cell
proliferation and digestive enzyme synthesis. The in situ hybridization method will be used to localize nucleic acids of
SIV and cytokines (IL-1, IL-2, IL-6, TNFalpha, TGFalpha, TGFbeta) in cells
of jejunal mucosa. Levels and biological activities of cytokines (IL-1,
IL-2, IL-6, TNFalpha) will be determined in jejunal mucosal homogenates.
Findings will be correlated with jejunal pathology, dysfunction and degree
of inflammation. Number of CD4+ helper and CD8+ suppressor T-lymphocytes
and macrophages will be measured by immunohistochemical staining to
determine populations of infiltrating mononuclear cells. Results obtained from the present proposal will define the role of
intestinal mucosal SIV infection in the development of SIV-associated
intestinal dysfunction. The research is aimed at elucidating the
pathogenesis of altered intestinal morphology and function in SIV infection
and determining the role of cytokines in this process. This information
will be relevant in the design of therapy directed at the mucosal lesion
early in the course of disease in an attempt to prevent malabsorption and
wasting.
StatusFinished
Effective start/end date3/1/9212/31/11

Funding

  • National Institutes of Health: $55,599.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $399,508.00
  • National Institutes of Health
  • National Institutes of Health: $52,115.00
  • National Institutes of Health: $16,003.00
  • National Institutes of Health: $298,194.00
  • National Institutes of Health: $332,267.00
  • National Institutes of Health
  • National Institutes of Health: $402,718.00
  • National Institutes of Health: $348,805.00
  • National Institutes of Health: $295,176.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $307,286.00
  • National Institutes of Health
  • National Institutes of Health: $55,599.00
  • National Institutes of Health
  • National Institutes of Health: $333,461.00

ASJC

  • Medicine(all)

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