HIV infection is the leading killer worldwide among infectious diseases, incurring ~2 million deaths annually. HIV has infected a total of more than 60 million people and over a third of them have died of AIDS. Defining the mechanisms of HIV transmission and understanding the role of immune cells and host factors that affect viral replication are essential in developing effective strategies to combat HIV infection. Our research focuses on the molecular mechanisms by which immune cells disseminate or restrict HIV infection. These studies can facilitate the development of more effective interventions against HIV infection and transmission.
SAMHD1-mediated HIV-1 restriction. Our major research interest centers on the molecular and cellular mechanisms underlying HIV-1 restriction by the host protein SAMHD1, which is the first identified mammalian dNTP triphosphohydrolase (dNTPase). Our previous work suggests that SAMHD1-mediated intracellular dNTP reduction is the primary mechanism of HIV-1 restriction in non-dividing cells (Antonucci J. et al. Nat. Med., 2016). We use combined approaches to further understand the physiological function of SAMHD1 and the mechanisms of SAMHD1-mediated retroviral restriction in myeloid cells, such as macrophages and dendritic cells.
HIV-1 RNA m6A modification. We have reported that N6-methyladenosine (m6A) modification of HIV-1 RNA regulates viral infection and HIV-1 protein expression in CD4+ T-cells (Tirumuru N. et al. eLife, 2016). We are investigating the molecular mechanisms by which m6A modification of HIV-1 RNA regulates viral gene expression in CD4+ T-cells. Because m6A-modified RNA has been found in other RNA or DNA viruses, this modification pathway may represent a novel and conserved target for broad antiviral development.
- Kodigepalli KM, Li M, Liu S-L, and Wu L. Exogenous expression of SAMHD1 inhibits proliferation and induces apoptosis in cutaneous T-cell lymphoma-derived HuT78 cells. Cell Cycle. 2017; 16(2):179-188. PMID: 27929746
- Kohnken R, Kodigepalli KM, Mishra A, Porcu P, and Wu L. MicroRNA-181 contributes to downregulation of SAMHD1 expression in CD4+ T-cells of Sèzary syndrome patients. Leukemia Research. 2017; 52: 58-66. PMID: 27889686
- St. Gelais C, Kim SH, Ding L, Yount J, Ivanov D, Spearman P, and Wu L. A putative cyclin-binding motif in human SAMHD1 contributes to protein phosphorylation, localization and stability. J. Biol. Chem. 2016; 291(51): 26332–26342. PMID: 27815502
- Antonucci J, St. Gelais C, de Silva S, Yount JS, Tang C, Ji X, Shepard C, Xiong Y, Kim B, Wu L. SAMHD1-mediated HIV-1 restriction in cells does not involve ribonuclease activity. Nature Medicine, 2016; 22: 1072–1074. PMID: 27711056
- Tirumuru N, Zhao B, Lu W, Lu Z, He C and Wu L. N6-methyladenosine of HIV-1 RNA regulates viral infection and HIV-1 Gag protein expression. eLife. 2016; 5:e15528. PMID: 27371828
- Bonifati S, Daly MB, St. Gelais C, Kim SH, Hollenbaugh JA, Shepard C, Kennedy EM, Kim DH, Schinazi RF, Kim B and Wu L. SAMHD1 controls cell cycle status, apoptosis and HIV-1 infection in monocytic THP-1 cells. Virology, 2016; 495: 92–100. PMID: 27183329
- Wang F, St. Gelais C, de Silva S, Zhang H, Geng Y, Shepard C, Kim B, Yount JS, Wu L. Phosphorylation of mouse SAMHD1 regulates its restriction of human immunodeficiency virus type 1 infection, but not murine leukemia virus infection. Virology. 2016; 487: 273-284. PMID: 26580513
- St. Gelais C, Roger J. Wu L. Non-POU domain-containing octamer-binding protein negatively regulates HIV-1 infection in CD4+ T-cells. AIDS Res Hum Retroviruses. 2015; 31(8):806-816. PMID: 25769457
- St. Gelais C, de Silva S, Hach JC, White TE, Diaz-Griffero F, Yount JS, Wu L. Identification of cellular proteins interacting with the retroviral restriction factor SAMHD1. J Virol. 2014; 88(10):5834-5844. PMID: 24623419
- de Silva S, Hoy H, Hake TS, Wong HK, Porcu P, Wu L. Promoter methylation regulates SAMHD1 gene expression in human CD4+ T cells. J Biol. Chem. 2013; 288(13): 92849292 PMID: 23426363
- St. Gelais C, de Silva S, Amie SM, Coleman CM, Hoy H, Hollenbaugh JA, Kim B, Wu L. SAMHD1 restricts HIV-1 infection in dendritic cells (DCs) by dNTP depletion, but its expression in DCs and primary CD4+ T-lymphocytes cannot be upregulated by interferons. Retrovirology. 2012; 9, 105. PMID: 23231760
- Coon S, Wang D, Wu L. Polymorphisms of the SAMHD1 gene are not associated with the infection and natural control of HIV-1 in African Americans and Europeans. AIDS Res Hum Retroviruses. 2012; 28(12): 1565-73. PMID: 22530776
- St. Gelais C, Coleman CM, Wang J-H, Wu L. HIV-1 Nef enhances dendritic cell-mediated viral transmission to CD4+ T cells and promotes T-cell activation. PLoS One. 2012; 7(3): e34521. PMID: 22479639
- Coleman CM, Spearman P, Wu L. Tetherin does not significantly restrict dendritic cell-mediated HIV-1 transmission and its expression is upregulated by newly synthesized HIV-1 Nef. Retrovirology. 2011; 8:26. PMID: 21504576
- Raghavendra NK, Shkriabai N, Graham RLJ, Hess S, Kvaratskhelia M, Wu L. Identification of host proteins associated with HIV-1 preintegration complexes isolated from infected CD4+ cells. Retrovirology. 2010; 7:66. PMID: 20698996