Characterization of the SAMHD1-mediated restriction to lentiviral infection counteracted by Vpx and analyzing its role in innate immunity
Final Report Abstract
Aicardi-Goutières syndrome (AGS) is a hereditary autoimmune disease that is characterized by spontaneous type I interferon (IFN) production. Among other genes, AGS can also be caused by defects of SAMHD1. SAMHD1 is dNTP triphosphohydrolase that regulates the intracellular dNTP content in a cell-cycle depend fashion. In addition, SAMHD1 acts as a retroviral restriction factor targeted by Vpx in myeloid cells. Within this project, we were able to significantly enhance our understanding of the antiviral restriction factor SAMHD1. We contributed to the finding that SAMHD1 restricts HIV in infected cells by hydrolyzing intracellular dNTPs and thereby lowering their concentrations below a threshold required for efficient reverse transcription. In addition, we also showed that SAMHD1 prevents the reverse transcription of HIV-1 RNA not only in non-dividing myeloid cells but also in resting CD4+ T cells. Also, we found that SAMHD1 restricts not only HIV and SIV but a wide array of divergent retroviruses, including the alpha, beta and gamma classes of retroviruses. Finally, we showed in gene-targeted mice that also murine SAMHD1 reduces cellular dNTP concentrations and restricts retroviral replication in lymphocytes, macrophages, and dendritic cells in vitro and in vivo. Together, this projected significantly contributes to our understanding of the nature and the mechanisms of the anti-HIV restriction factor SAMHD1. Our findings might therefore be used to identify novel soft spots of retroviral replication that could be targeted by antiviral drug development. In addition, the characterization of the functions of SAMHD1 in mice led to the establishment of the SAMHD1 KO mice model as tool to characterize the role of SAMHD1 in viral replication in vivo and to analyze the role of SAMHD1 in preventing the auto immune disease Aicardi-Goutières syndrome.
Publications
- SAMHD1 restricts HIV-1 infection in resting CD4(+) T cells, Nature Medicine 18(11):1682-7, 2012
Baldauf H.M., Pan X., Erikson E., Schmidt S., Daddacha W., Burggraf M., Schenkova K., Ambiel I., Wabnitz G., Gramberg T., Panitz S., Flory E., Landau N.R., Sertel S., Rutsch F., Lasitschka F., Kim B., König R., Fackler O.T., Keppler OT.
(See online at https://doi.org/10.1038/nm.2964) - SAMHD1 restricts the replication of human immune-deficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates, Nature Immunology Feb 12;13(3):223-8, 2012
Lahouassa H., Daddacha W., Hofmann H., Ayinde D., Logue E.C., Dragin L., Bloch N., Maudet C., Bertrand M., Gramberg T., Pancino G., Priet S., Canard B., Laguette N., Benkirane M., Transy C., Landau N.R., Kim B., Margottin-Goguet F.
(See online at https://doi.org/10.1038/ni.2236) - Mouse SAMHD1 Has Antiretroviral Activity And Suppresses A Spontaneous Cell Intrinsic Antiviral Response, Cell Reports 4(4):689-96, 2013
Behrendt R., Schumann T., Gerbaulet A., Nguyen L.A., Schubert N., Alexopoulou D., Berka U., Lienenklaus S., Peschke K., Gibbert K., Wittmann S., Lindemann D., Weiss S., Dahl A., Naumann R., Dittmer U., Kim B., Mueller W., Gramberg T., Roers A.
(See online at https://doi.org/10.1016/j.celrep.2013.07.037) - Restriction of diverse retroviruses by SAMHD1, Retrovirology 2013 Mar 5; 10:26
Gramberg T., Kahle T., Bloch N., Wittmann S., Müllers E., Lindemann D. and Landau N.R.
(See online at https://doi.org/10.1186/1742-4690-10-26)
