To develop methods for evaluating the size and complexity of recirculating lymphocyte pools in infected and uninfected rhesus macaques. RESULTS SIV disease in macaques models the persistent lymphadenopathy observed in HIV infection in man. Preferential lymphocyte trafficking to lymph nodes and increased sequestration of recirculating lymphocytes in these active tissues may account for some of the declining CD4 cell levels that occur during persistent infection. Lymphocyte trafficking is regulated by increased expression of cell-surface adhesion molecules and by responses to chemokines produced locally at sites of immune activation. Pertussis toxin interrupts the G-protein signaling pathway that recognizes chemokine binding to the seven-transmembrane receptors on cell surfaces. This biochemical mechanism interrupts a key step in lymphocyte trafficking to nodes and induces a profound but transient lymphocytosis. Analysis of blood cell levels during lymphocytosis showed that declining blood CD4 cell levels were due mainly to increased proportion of this population residing in tissues. There was no evidence for a net loss of CD4 cells during the period of asymptomatic infection of macaques. Once the CD4 count declined below 300 cells per 5l of blood, than we detected a rapid, net loss of cells from both blood and tissue compartments. Studies continue with pertussis toxin in macaques to test other mechanisms that regulate blood cell count and to understand mechanisms for CD4 cell regulation during acute SIV infection. FUTURE DIRECTIONS Apply pertussis toxin treatment to our study of acute SIV or SHIV infection of macaques. Pertussis toxin is reported to have the capacity to block activation induced cell death in vitro and we believe this mechanism is important for AIDS pathogenesis in vivo. We will treat with pertussis toxin during acute infection and test whether the intervention prevents indirect CD4 cell depletion that may occur by an apoptosis mechanism. KEY WORDS AIDS, therapy, immunomodulator FUNDING NIH R01 AI38491
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