We have recently demonstrated that the intestinal tract is the principle target of CD4 depletion in macaques acutely infected with SIV Using PMPA as a therapeutic tool to manipulate viral loads, we are determining the capacity, kinetics, and characterization of mucosal CD4+ T cell restoration by four color flow cytometry on serial intestinal biopsies from animals at various stages of SIV infection A total of five SIV-infected macaques have been examined Three were chronically infected before therapeutic intervention One macaque was infected for 7 days before treatment intervention, and another macaque was infected and followed as an untreated control to monitor unimpeded mucosal CD4+ T cell depletion All animals were monitored at weekly intervals for several weeks before, during, and after treatment intervention Duodenal, colonic, and peripheral lymph node biopsies and blood were analyzed by 4-color flow cytometry to detect changes in the composition of t he i ntestinal immune response and CD4+ T cell restoration In two of the three chronically infected animals, mucosal CD4+ T Cells were not restored despite 28 days of PMPA therapy While all three animals showed a 3 log decrease in viral loads, only one of the animals demonstrated a rebound in mucosal CD4+ T cells in the intestine Furthermore, these CD4+ T cells co-expressed markers of cellular activation and """"""""memory"""""""" This animal became moribund necessitating euthanasia a few days after cessation of PMPA therapy Histopathology revealed an atypical, highly inflammatory disseminated Mycobacterium avium infection in the intestine We hypothesize that the excessive inflammatory response was the result of restoration of the animals CD4+ T cells which led to a potent and detrimental immune response to the M avium In acutely infected animals, intestinal CD4 depletion occurred rapidly in both the untreated control and in the one given delayed PMPA treatment However, activated, mucosal CD4+ T cells were promptly re-established in the intestine shortly after the initiation of therapy These results suggest that while mucosal CD4+ T cells may be fully restored in the early stages of infection, there may be limitations on the capacity of CD4+ T cell + restoration in chronically infected patients
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