Expression of the recently discovered human restriction factor SAMHD1 is responsible for the infection block imposed to lentiviruses such as HIV-1, HIV-2 and SIVmac by primary macrophages, dendritic cells and resting CD4+ T-cells. SAMHD1 blocks lentiviral infection by preventing the occurrence of reverse transcription. The viral accessory protein Vpx, contained in SIVmac and HIV-2 particles, overcomes the SAMHD1 reverse transcription block by inducing SAMHD1 degradation. SAMHD1 is a dGTP-regulated deoxynucleotide triphosphohydrolase that decreases the cellular levels of triphosphodeoxynucleotides (dNTPs). Interestingly, cycling and non-cycling cells express SAMHD1; however, SAMHD1's antiviral activity is only observed in non- cycling cells. Our preliminary findings correlate the lentiviral restriction phenotype observed in non-cycling cells with the phosphorylation and S-glutathionylation state of SAMHD1. This proposal will test the hypothesis that SAMHD1 antiviral activity is regulated by phosphorylation and S-glutathionylation. The following specific aims will be used to address this hypothesis.
Aim1 will explore the role of SAMHD1 phosphorylation in retroviral restriction.
Aim 2 will explore the role of S-glutathionylation in retroviral restriction.
Aim 3 will explore the role of SAMHD1 in the type I IFN response. Overall, this proposal will establish the regulation of SAMHD1 antiviral activity. Understanding the regulation of SAMHD1 is instrumental for the development of novel anti-HIV-1 vaccine strategies since overcoming SAMHD1 increases the adaptive immune response during infection of dendritic cells and macrophages.
SAMHD1 is a restriction factor that blocks HIV-1 infection in macrophages and dendritic cells. However, SAMHD1 only blocks HIV-1 infection in non-cycling cells. This work will attempt to understand the regulation of SAMHD1 in both cycling and non-cycling cells. Understanding this regulation will be instrumental for the development of novel anti-HIV-1 vaccine strategies since overcoming SAMHD1 increases the adaptive immune response during HIV-1 infection of macrophages and dendritic cells.
|Wang, Zhonghua; Bhattacharya, Akash; White, Tommy et al. (2018) Functionality of Redox-Active Cysteines Is Required for Restriction of Retroviral Replication by SAMHD1. Cell Rep 24:815-823|
|Schott, Kerstin; Fuchs, Nina V; Derua, Rita et al. (2018) Dephosphorylation of the HIV-1 restriction factor SAMHD1 is mediated by PP2A-B55? holoenzymes during mitotic exit. Nat Commun 9:2227|
|Schulte, Bianca; Selyutina, Anastasia; Opp, Silvana et al. (2018) Localization to detergent-resistant membranes and HIV-1 core entry inhibition correlate with HIV-1 restriction by SERINC5. Virology 515:52-65|
|Martinez-Lopez, Alicia; Martin-Fernandez, Marta; Buta, Sofija et al. (2018) SAMHD1 deficient human monocytes autonomously trigger type I interferon. Mol Immunol 101:450-460|
|Buffone, Cindy; Martinez-Lopez, Alicia; Fricke, Thomas et al. (2018) Nup153 Unlocks the Nuclear Pore Complex for HIV-1 Nuclear Translocation in Nondividing Cells. J Virol 92:|
|Opp, Silvana; Fricke, Thomas; Shepard, Caitlin et al. (2017) The small-molecule 3G11 inhibits HIV-1 reverse transcription. Chem Biol Drug Des 89:608-618|
|White, Tommy E; Brandariz-Nuñez, Alberto; Martinez-Lopez, Alicia et al. (2017) A SAMHD1 mutation associated with Aicardi-Goutières syndrome uncouples the ability of SAMHD1 to restrict HIV-1 from its ability to downmodulate type I interferon in humans. Hum Mutat 38:658-668|
|White, Tommy E; Brandariz-Nuñez, Alberto; Han, Kyudong et al. (2016) Modulation of LINE-1 Retrotransposition by a Human SAMHD1 Polymorphism. Virol Rep 6:53-60|