Basic Science Award

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.

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.

Invariant natural killer T (NKT) cells are innate-like T cells that respond to lipid antigens presented on the MHC class I-like molecule CD1d. These immunoregulatory cells have the capacity for abundant cytokine release almost immediately after antigen recognition and are essential for the activation of multiple arms of the immune response, including dendritic cells, conventional T cells and B cells. Murine studies have shown that the intestinal microbiome is an important factor in the maturation of functional NKT cells.

Detection of gene expression by flow cytometry is currently limited to transcripts that are abundantly expressed, however the recently reported RNAscope technology offers greatly improved sensitivity and specificity and has the potential to change the approach to single-cell transcript measurements that currently require low sensitivity approaches and are extremely low throughput. As yet these probes have not been utilized for study of patient samples by flow cytometry.

The depletion of CD4 T cells and the development of chronic inflammation are signature processes in HIV pathogenesis that propel progression to AIDS. Our recent ex vivo studies have revealed how most lymphoid CD4 T cells die by caspase-1-mediated-pyroptosis, an intensely inflammatory form of programmed cell death, providing an unexpected association between these two disease-promoting processes.

Progressive depletion of CD4 T cells is a hallmark of untreated acquired immune deficiency syndrome (AIDS), but the mechanism of CD4 T-cell death by HIV remains poorly understood. While HIV 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 better understand how HIV infection depletes CD4 T cells, we used primary human lymphoid aggregate cultures (HLAC) from human tonsil and spleen tissue. Using this system three surprising discoveries emerged.