This proposal will use a cohort of injection drug users to evaluate the hypothesis that progression of HIV-1 infection is attributable to 1) the ability of the virus to spread to new cells and 2) the rate of viral replication in cells that are already infected. Both of these processes require some form of broadly reactive T-cell activator (PHA, anti-CD3, IL-2) to proceed efficiently in vitro, and it is our hypothesis that similar activation is required in vivo, as well. The absence of such activation in the naive host may explain the restricted viral genetic heterogeneity observed in newly infected individuals. We hypothesize that the source of the stimulation in ongoing viral infection is the virus itself and that differences in the course of infection, as measured by CD4 T cell decline and time to AIDS, can be attributed to differences in the ability of different viral variants to induce cellular activation, which in turn permits viral replication and spread. Dividing the AIDS Linked to the Intravenous Experience cohort of injection drug users into groups of rapid progressors, moderate progressors, and slow progressors, we will prospectively follow and compare four parameters in 60 individuals from the ALIVE cohort: 1) the development of genetic variation over time in the third hypervariable domain of the viral envelope 2) the ability of viral variants to elicit tumor necrosis factor-a alpha from host cells and 3) the ability of virus to stimulate proliferation of host cells. We hypothesize that genetic variation can serve as a measure of viral spread since such variation occurs predominantly during the reverse transcription that occurs when new cells are infected. Our preliminary data suggest that such variation increases as CD4 T cell levels decline in the majority of HIV-1 infected subjects and in this proposal we seek to extend and confirm the relevance of this observation to groups progressing at different rates. We seek to show a correlation between CD4 decline and variation and a correlation between rate of CD4 decline and rate of appearance of variation. Our preliminary data also show that low passage viral variants differ in their ability to elicit TNF-alpha secretion, which directly activates viral replication, and to stimulate T cell proliferation, which enhances viral reverse transcription and integration in the host cell genome. We will therefore analyze differences in these capabilities among low passage viruses obtained from the study cohort. By establishing the critical influence of the activating properties of different viral variants on the course of HIV-1 progression, these studies will provide important insights into HIV-1 pathogenesis and provide a new target for therapeutic strategies directed to slowing the progression of this disease.
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