Basic Science Award

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.

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.

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.