Mechanistic analysis of HIV restriction by SAMHD1
The SAM and HD domain-containing protein SAMHD1 is a dNTP hydrolase that plays a role in nucleic acid metabolism by converting dNTPs to deoxynucleosides and inorganic triphosphate. Human SAMHD1 has been identified as a component of the innate immune system that restricts HIV-1 infection in myeloid cells, such as macrophages, and resting CD4+ T cells. It has been suggested that SAMHD1 blocks HIV infection in non-cycling cells by lowering the cellular dNTP concentration below the level required for reverse transcription. In dividing cells, however, the antiviral activity of SAMHD1 is regulated and blocked by phosphorylation at Thr592 by cellular cell-cycle dependent kinases. However, the enzymatic activity of SAMHD1 was found to be independent of phosphorylation, suggesting an alternative unknown mechanism of restriction. Thus, we will design and use various recombinant HIV-based viruses as well as different SAMHD1 mutants to study the interplay between SAMHD1 and HIV-1 and solve the puzzle how SAMHD1 blocks infection of HIV-1 and how the virus overcomes this barrier.
Together, this project will contribute to the understanding of the mechanism of the SAMHD1-mediated restriction of HIV-1 and will therefore uncover a novel Achilles heel of the virus, which might be targeted by future antiviral drug development.
