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.

The depletion of CD4 T cells and development of chronic inflammation represent signature pathological processes centrally contributing to clinical progression of HIV disease. Current therapy chiefly diminishes viral replication. Novel therapeutics preventing CD4 T-cell depletion and/or reducing chronic inflammation could form valuable adjuncts to antiviral medications potentially improving long-term clinical outcomes including limiting the early appearance of diseases associated with aging. Our studies suggest that these signature processes are, in fact, interrelated.

Although macrophages are important in vivo targets for Human Immunodeficiency Virus Type 1 (HIV-1) infection, their relevance for the transmission, spread, and pathogenesis of HIV-1 remains unclear. This may be due to heterogeneity in subpopulations of macrophages, such that some but not all are permissive for infection. In part, this tropism could be related to tissue localization, but cell-intrinsic restriction factors, such as APOBEC3 and SAMHD1, have also recently been shown to exhibit direct antiviral activity.

The antibody repertoire (AbR) is a component of the adaptive immune system that is capable of undergoing real-time coevolution with infectious pathogens. I aim to characterize the genetic interaction that takes place between the AbR and HIV over the course of acute infection and to infer coevolutionary genetic signatures to detect the specific loci engaged in this interaction. My approach has the potential to provide a systems level view of all AbR/HIV interacting sites and will illuminate how these interactions change over time.

We have previously shown that infection-impaired HIV with incompletely processed capsid-spacer protein 1 (CA-SP1) is rescued by either cellular activation or increased expression of HSP90AB1, a member of the cytosolic heat shock protein 90 family of cellular chaperones. Expanding on our initial results, we found that HSP90AB1 is present in HIV virions and that recombinant HSP90AB1, but not nonfunctional mutated HSP90AB1E42A+D88A, restores infectivity to HIV with mutations in CA that alter core stability and impair infectivity.