A fundamental issue in the pathogenesis of AIDS regards the primary factors which influence viral burden during disease progression. As the major reservoirs for HIV-1 replication, CD4+ T lymphocytes and macrophages play a central role in the maintenance of viral burden, however, replication of HIV-1 within these cells is profoundly influenced by their activation state. As an extension of this, opportunistic pathogens of the lung may influence HIV replication in infected individuals directly by activation of HIV replication in lung macrophages. Additionally, cytokines released from activated macrophages may indirectly activate HIV replication in CD4+T lymphocytes. Either scenario would exacerbate viral burden in the infected individual. The approach to be taken in examining activation of HIV-1 by antigens of Streptococcus pneumoniae, a major lung pathogen, stems from our recent observations that pneumococcal vaccination of HIV-1 infected individuals leads to significant yet transient increases in viral burden. This proposal aims to examine how pneumococcal antigens influence HIV replication in macrophages and CD4+T lymphocytes and additionally to identify viral and cellular determinants which mediate this effect. Specifically we propose to: 1. Examine the effect of pneumococcal antigens on HIV-1 replication in macrophages in vitro. 2. Examine role of CD4+ T lymphocytes in activation of HIV by antigens of S. pneumoniae. 3. Examine impact of pneumococcal vaccination and acute pneumococcal infection on viral burden in HIV-1 infected individuals. It is expected that these studies will provide insight into how opportunistic pathogens of the lung impact HIV replication and further delineate the mechanism of HIV-1 activation.
