Basic Science Award

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.

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 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.

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.