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.

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.

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.

There remains a subset of HIV-infected patients who maintain undetectable plasma HIV RNA levels (elite controllers) that make up approximately 1% of the HIV-infected population. The mechanism for this unique status is the subject of intensive research, but remains unknown. The objective of this proposal is to determine how a set of six cytokines found to be elevated in the serum of HIV elite controllers influences viral replication and cellular activation.

The continuing spread of HIV/AIDS in people is predominantly fueled by sexual exposure to HIV-contaminated semen/seminal plasma (SP). SP harbors HIV infectivity enhancing factors that include at least two major classes of naturally occurring amyloid fibrils that promote virion attachment to cellular targets. SP also harbors a variety of pro-inflammatory factors that can indirectly facilitate HIV transmission by promoting the production of cytokines/chemokines that recruit permissive cells, enhance the translocation of HIV across the genital epithelium, and activate HIV gene transcription.

Sexual transmission accounts for most cases of HIV infection worldwide, with semen being the main carrier of viral particles during this process. Recent studies revealed that positively charged amyloid fibrils from human semen can substantially boost HIV infectivity rates. In two separate studies, M?nch et al. and our group identified two distinct HIV-enhancing semen amyloids.

The continuing spread of HIV/AIDS in people is predominantly fueled by sexual exposure to HIV-contaminated semen/seminal plasma (SP). SP harbors HIV infectivity enhancing factors that include at least two major classes of naturally occurring amyloid fibrils that promote virion attachment to cellular targets. SP also harbors a variety of pro-inflammatory factors that can indirectly facilitate HIV transmission by promoting the production of cytokines/chemokines that recruit permissive cells, enhance the translocation of HIV across the genital epithelium, and activate HIV gene transcription.