The reservoir of cells harboring latent HIV-1 precludes a cure of infection by existing anti-HIV drugs. The best described latent reservoir is that of long-lived memory CD4+ T cells. Multiple mechanisms are thought to be involved in HIV latency in these cells: repressive chromatin;transcriptional interference by cellular genes;limiting levels of cellular transcriptio factors, especially the transcriptional elongation factor termed P-TEFb. We propose to develop methods to selectively up-regulate P-TEFb in resting CD4+ T cells, as well as to demonstrate associations in vivo between regulation of P-TEFb and HIV latency. In the R21 phase of the proposed research, we will determine if selective up-regulation of P-TEFb, either alone or in synergy with other latency activating agents, can reactivate latent HIV in a primary CD4+ T cells model of latency. In the R33 phase of the work, we will determine if selective up-regulation of P-TEFb, either alone or in combination with other agents, can reactivate latent HIV in patients'samples. To investigate P-TEFb and HIV latency in vivo, we will utilize immunohistochemistry (IHC) and RNA in situ hybridization (ISH) to examine lymph node and brain samples from HIV- infected individuals, both before and after anti-viral therapy. The proposed work has the potential to establish an association in vivo between the regulated expression of P-TEFb and HIV replication and latency. Importantly, the proposed work has the potential to establish that selective up-regulation of P-TEFb is a feasible strategy to reactivate latent HIV in vivo.
We will develop strategies to reactivate latent HIV-1 in a model system of primary CD4+ T cells, as well as in patients'CD4+ T cells ex vivo. We will also determine if there is an association of HIV replication and latency with the regulation expression of a cellular co-factor known as P-TEFb. Our research may contribute to strategies to cure infection.
|Kimata, Jason T; Rice, Andrew P; Wang, Jin (2016) Challenges and strategies for the eradication of the HIV reservoir. Curr Opin Immunol 42:65-70|
|Rice, Andrew P (2016) Cyclin-dependent kinases as therapeutic targets for HIV-1 infection. Expert Opin Ther Targets 20:1453-1461|
|Jamaluddin, Md Saha; Hu, Pei-Wen; Jan, Yih et al. (2016) Short Communication: The Broad-Spectrum Histone Deacetylase Inhibitors Vorinostat and Panobinostat Activate Latent HIV in CD4(+) T Cells In Part Through Phosphorylation of the T-Loop of the CDK9 Subunit of P-TEFb. AIDS Res Hum Retroviruses 32:169-73|
|Rice, Andrew P; Kimata, Jason T (2015) Subversion of Cell Cycle Regulatory Mechanisms by HIV. Cell Host Microbe 17:736-40|