Keppler Lab - Research
Intrinsic Immunity and Control of Retroviral Infection
Besides classical innate and acquired immune responses, mammals have evolved a set of genes that are capable of suppressing or preventing virus replication at the cellular level.
These so called restriction factors, which are frequently up-regulated by host cells in response to virus infection, appear to impose particularly effective barriers in the context of cross-species transmission of viruses. Accordingly, they have been classified as “intrinsic” immunity, representing an innate cellular network for the front-line defense in an immunologically naïve host.
SAMHD1 was recently identified as a restriction factor, the expression of which prevents the completion of HIV-1 reverse transcription in macrophages and dendritic cells. Recently, we and others were able to show that SAMHD1 also acts as a restriction factor in resting CD4 T cells, expanding the relevant cell pool from myeloid to lymphoid cells. The mode of action of this deoxynucleotide triphosphohydolase appears to be primarily the depletion of intracellular dNTP pools below a threshold required for reverse transcription of the viral RNA into complementary DNA.
HIV encodes a unique set of accessory gene products (Vif, Nef, Vpr, Vpu, Vpx) to optimize its replication in the human host. Knowledge gained over the last years suggests that this is achieved, in part, by counteracting host restriction factors, including APOBEC3, CD317/Tetherin, SAMHD1 and SerinC5.
Using state-of-the art techniques from molecular virology, cell biology, immunology and biochemistry, our laboratory pursues the following goals:
- Elucidate the mechanisms by which known and newly identified restriction factors induce a potent block for virus replication of HIV-1 and other pathogenic viruses
- Decipher how accessory viral proteins mediate their antagonistic function
- Establish the relevance of restriction factors for HIV transmission and pathogenesis
- Shed light on the virus-host coevolution and the regulation of cross-species transmission