Basic Science Award

Progressive depletion of CD4 T cells is a hallmark of HIV/SIV-induced AIDS. While HIV/SIV directly infects and kills CD4 T cells, the number of productively infected cells in vivo cannot account for the massive CD4 T-cell losses that occur. To gain a better understanding of this phenomenon, primary human lymphoid aggregate cultures (HLAC) from human tonsil and spleen tissue were examined. Three surprising discoveries emerged.

Progressive depletion of CD4 T cells is a hallmark of HIV/SIV-induced AIDS. While HIV/SIV directly infects and kills CD4 T cells, the number of productively infected cells in vivo cannot account for the massive CD4 T-cell losses that occur. To gain a better understanding of this phenomenon, primary human lymphoid aggregate cultures (HLAC) from human tonsil and spleen tissue were examined. Three surprising discoveries emerged.

Understanding the mechanism of HIV-1 transcription is key for developing a new class of antiviral drugs. HIV-1 Tat is an essential protein that transactivates HIV transcription by binding to the TAR region of HIV mRNA. p300-mediated acetylation of Tat is required for transactivation of the HIV long terminal repeat. Full activation of the HIV promoter also requires nuclear factor kappa-B (NF!B), which activates HIV transcription. Full activation of NF_B also requires p300-mediated acetylation.

Understanding the mechanism of HIV-1 transcription is key for developing a new class of antiviral drugs. HIV-1 Tat is an essential protein that transactivates HIV transcription by binding to the TAR region of HIV mRNA. p300-mediated acetylation of Tat is required for transactivation of the HIV long terminal repeat. Full activation of the HIV promoter also requires nuclear factor kappa-B (NF!B), which activates HIV transcription. Full activation of NF_B also requires p300-mediated acetylation.

HIV-infected individuals are at increased risk for a number of diseases typically associated with aging, including cardiovascular disease. It is now well accepted that poorly defined HIV-associated immunologic perturbations, in addition to traditional risk factors and antiretroviral therapy toxicity, contribute to this risk. This study will explore the pathogenesis of HIV-associated cardiovascular disease with a focus on telomere maintenance and aging.

HIV-infected individuals are at increased risk for a number of diseases typically associated with aging, including cardiovascular disease. It is now well accepted that poorly defined HIV-associated immunologic perturbations, in addition to traditional risk factors and antiretroviral therapy toxicity, contribute to this risk. This study will explore the pathogenesis of HIV-associated cardiovascular disease with a focus on telomere maintenance and aging.

HIV relies heavily on remodeling host regulatory networks for its replication. One major target of this remodeling process is the cellular ubiquitin machinery, which modifies proteins by adding ubiquitin moieties to target them for degradation and to modulate their activities. HIV exploits the ubiquitination system as a means to interfere with crucial antiviral pathways and immune mechanisms. Therefore, targeting interactions between HIV proteins and the human ubiquitin machinery is a promising direction for developing new anti-HIV therapeutics.

CD8+ T cells play an important role in inhibiting HIV replication through a non-cytotoxic antiviral activity. This response is mediated by a soluble CD8+ T cell anti-HIV factor (CAF). Several studies have shown that all known anti-HIV factors lack identity with CAF. CAF appears to be a novel anti-HIV protein. A great effort has been given to evaluating the gene candidates associated with CAF identified by DNA microarray procedures. The list of potential genes was narrowed down to twenty-five.

As an obligatory intracellular parasite with limited genome size, retroviruses interact with both supportive and inhibitory host factors to complete their life cycle. Inhibitory factors could, in principle, intervene against the virus at every step of replication and are collectively called host restriction factors. Preliminary data indicated that human Piwil2 inhibited HIV replication at the step of HIV protein synthesis. Our objective is to understand the anti-HIV mechanism of Piwil2 and evaluate its physiological roles in cells or tissues with high levels of Piwil2.

One of the remaining questions in HIV research is how the virus establishes a dormant (latent) state and thereby escapes eradication by current antiretroviral therapy. Latently infected T cells do not produce significant amounts of viral genomes or proteins due to the silencing of a specific step in the virus life cycle?viral transcription. Viral transcription can be reactivated in latently infected cells, a process that rekindles HIV infection after antiretroviral therapy is discontinued and remains a major barrier to eradication.