OMB No. 0925-0001 and 0925-0002 (Rev. 10/15 Approved Through 10/31/2018) BIOGRAPHICAL SKETCH NAME: Yuyang Tang eRA COMMONS USER NAME (credential, e.g., agency login): YUTANG
POSITION TITLE: Research Assistant Professor
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.) DEGREE Completion (if Date FIELD OF STUDY INSTITUTION AND LOCATION applicable) MM/YYYY
Hunan Normal University, Changsha,Hunan,China BS 07/1994 Biology Peking Union Medical College,Beijing,China MS 07/1997 Cellular Biology Peking Union Medical College,Beijing,China PhD 07/2000 Immunology& microbiology Emory University, Atlanta, GA Postdoc 12/2002 Virology University of North Carolina in Chapel Hill Postdoc 07/2007 Virology
A. Personal Statement I have pursued a range of studies within HIV virology and pathogenesis over more than 10 years, but my recent research has focused on the study of non-conventional HIV-1 (HIV) entry mechanism and development of anti-viral strategies. We demonstrated that when HIV replicates in the presence of other pathogenic viruses such as HTLV-1, HIV produced from co-infected cells can have expanded cell tropism and is able to directly infect primary female vaginal and cervical epithelial cells. These cells do not express HIV receptor CD4 and normally are impervious to HIV. The molecular mechanism has been linked to HTLV-1 envelope glycoproteins that are pseudotyped on HIV particles. We also found that HIV from HTLV-1/HIV co-infected donors can infect epithelial cells, indicating that pseudotyped HIV could occur in vivo, and may facilitate HIV sexual transmission in regions where these two retroviruses are co-endemic. In addition, our study has established that human endogenous retroviral Envs residing in host cells could also expand HIV cell tropism. It was during this work that my collaboration with the Brazilian group began, and has led to the current application. Our recent findings show that human endogenous retroviral Env, syncytin which is naturally expressed in human placenta barrier cells, was able to direct HIV infection of these non-CD4 expressing host cells, by either pseudotying HIV or by inducing cell fusion with infected immune cells. These findings have critical clinical implications as non-conventional HIV entry mechanisms could allow HIV to overcome host cell barriers, or facilitate the establishment of reservoirs and/or latency alternate host cells. More recently in collaboration with Drs. Jiang, Dandekar and Margolis, I have studied approaches to HIV cure. We have an ongoing project to study syncytin reactivation in HIV positive patients with HIV-associated neurocognitive disorders (HAND) and its role in HIV persistence in the central nerve system (CNS). This study is built on our preliminary observations that abnormal syncytin expression was associated with HAND. Syncytin induction in the brain of HAND patients is possible due to the chronic HIV infection-induced immune activation. We will explore the association of syncytin expression with HAND progression and investigate how syncytin modulates HIV infection in the CNS. I believe our expertise in study of non-conventional HIV entry and the great resources in UNC HIV Cure Center will advance our knowledge of how HIV infects the CNS and how HIV positive patients develop HAND.
B. Positions and Honors Positions and Employment 2007-2011: Senior Research Associate, Center for AIDS Health Disparities Research, Vanderbilt-Meharry Center for AIDS Research, Meharry Medical College, Nashville, TN 2011-2016: Assistant Project Scientist, Department of Molecular and Cellular Biology. University of California, Davis 2016-2019: Assistant Project Scientist, Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis 2019 February-current: Research Assistant Professor of Medicine in UNC HIV Cure center, University of North Carolina at Chapel Hill Honors 2018 Academic Senate Research Travel Award Program, University of California, Davis 2015 Academic Senate Research Travel Award Program, University of California, Davis 2010 Vanderbilit University StarBRITE award (VR271) 2008 Vanderbilit University StarBRITE award (VR1788) 2007 CROI2007 Young Investigator Award
C. Contribution to Science 1. Novel molecular mechanisms influence viral transmission and HIV tissue reservoirs. We have recently defined two routes of HIV infection that expand HIV cell tropism and enable it to directly infect host cells that are normally non-permissive to HIV. We observed that HIV can harbor the sexually co- infected viral Env (such as HTLV-1 Env) during co-infection and form pseudotyped viruses to directly infect genital tract epithelial cells thereby overcome the host mucosal cellular barriers to facilitate sexual transmission. We further revealed that HIV can use endogenous retroviral Env (syncytin) residing on host cell membrane for its cell-to-cell route of viral dissemination. This new route of infection enables HIV to infect multiple cell types including non-CD4 expressing host cell. Our data support that syncytin, which is naturally expressed in placental trophoblasts, drives HIV infection of these placental barrier cells for transplacental HIV transmission. We have recently detected expression of syncytin in the brain of HAND patients, which raises the possibility that syncytin-mediated entry potentially is a novel risk factor to drive HIV dissemination in the central nervous system and contribute to HAND progression during chronic infection of HIV. a. Tang Y, George AM, Petrechko O, Nouvet FJ, Sweet SD, Tanaka Y, Imbiakha BS, Jiang G, Gao W, Anastos K, et al. Pseudotyping of HIV-1 with Human T-Lymphotropic Virus 1 (HTLV-1) Envelope Glycoprotein during HIV-1-HTLV-1 Coinfection Facilitates Direct HIV-1 Infection of Female Genital Epithelial Cells: Implications for Sexual Transmission of HIV-1. mSphere. 2018;3(2). We reported that HIV-1 was pseudotyped by HTLV-1 Env during their co-infection, which enable HIV to directly infect primary mucosal epithelial cells from female genital tract. These cells constituted genital mucosal barrier and normally were resistant to HIV-1. We provided the first evidence that HIV- 1 derived from HIV-1/HTLV-1 co-infected patients had expanded cell tropism for CD4 negative epithelial cells, indicating that HTLV-1 Env pseudotyping of HIV-1 occurred in vivo. We concluded that pseudotyping is a novel risk factor to drive HIV-1 spread in the areas where the co-infection is common. b. Tang Y, George A, Nouvet F, Sweet S, Emeagwali N, Taylor HE, Simmons G, and Hildreth JE. Infection of female primary lower genital tract epithelial cells after natural pseudotyping of HIV-1: possible implications for sexual transmission of HIV-1. PloS one. 2014;9(7):e101367.
2. HIV Vaccine development. I have made contribution to development of an HIV vaccine by using DNA and MVA prime-boost strategy in Dr. Harriet Robinson’s laboratory at Emory University. This vaccine has been moved to Phase II clinical trial and the potential success of this vaccine also resulted in the formation of GeoVax Inc, a biotechnology company developing human vaccines against infectious diseases. I have also developed a single cycle SIV vaccine and contributed to a VEE vector based SIV glycoprotein vaccine candidate, both of which were advanced to rhesus macaque studies. a. Tang Y, Villinger F, Staprans SI, Amara RR, Smith JM, Herndon JG, Robinson HL.. Slowly declining levels of viral RNA and DNA in DNA/recombinant modified vaccinia virus Ankara-vaccinated macaques with controlled simian-human immunodeficiency virus SHIV-89.6P challenges. Journal of Virology, 2002, 76: 10147-10154 b. Tang Y, Swanstrom R. Development and characterization of a new single cycle vaccine vector in the simian immunodeficiency virus model system. Virology. 2008, 372:72-84 c. Fluet ME, Whitmore AC, Moshkoff DA, Fu K, Tang Y, Collier ML, West A, Moore DT, Swanstrom R, Johnston RE, Davis NL. Effects of rapid antigen degradation and VEE glycoprotein specificity on immune responses induced by a VEE replicon vaccine. Virology. 2008, 370:22-32
3. HIV therapeutic drug development. I also contributed to the study of anti-HIV latency compounds with with Drs. Satya Dandekar and Guochun Jiang at the University of California, Davis. We have discovered that Ingenol compounds are able to potently reactivate latent HIV reservoirs. Our recent study regarding the compound PEP005 has been reported by BBC with the title: “HIV flushed out by cancer drug” (Linker for BBC News:http://www.bbc.com/news/health-33720325). In vivo animal model studies and a human trial are ongoing now. a. Jiang G, Nguyen D, Archin NM, Yukl SA, Mendez-Lagares G, Tang Y, Elsheikh MM, Thompson GR, 3rd, Hartigan-O'Connor DJ, Margolis DM, Dandekar S. HIV latency is reversed by ACSS2- driven histone crotonylation. The Journal of Clinical Investigation. 2018;128(3):1190-8. b. Jiang G, Santos Rocha C, Hirao LA, Mendes EA, Tang Y, Thompson GR, 3rd, et al. HIV Exploits Antiviral Host Innate GCN2-ATF4 Signaling for Establishing Viral Replication Early in Infection. mBio. 2017;8(3). c. Jiang G, Erica A. Mendes, Phillip Kaiser, Tang Y, Ivy CAI, Anne Fenton, Greg P. Melcher, James E. K. Hildreth, George R. Thompson, Joseph K. Wong and Satya Dandekar. Synergistic reactivation of latent HIV expression by PEP005 targeted NF-kB signaling in combination with JQ1 induced p-TEFb production. PLoS Pathog. 2015 Jul 30;11(7):e1005066. d. Jiang G, Mendes E, Kaiser P, Sankaran-Walters S, Tang Y, Weber, Mariana G, Melcher GP; Thompson GR III, Tanuri A, Pianowski L, Wong J, Dandekar S. Reactivation of HIV latency by a newly modified Ingenol derivative via protein kinase Cδ-NF-κB signaling. AIDS. 2014 Jul 17;28(11):1555-66
4. Evaluation of HIV variants regarding to compartmentalization and transmission. I have contributed to a serial of studies to evaluate HIV sequence variation analysis regarding to HIV compartmentalization, replication and transmission. I did extensive single genome PCR and sequence analysis for these studies. a. Ping LH, Joseph SB, Anderson JA, Abrahams MR, Salazar-Gonzalez JF, Kincer LP, Treurnicht FK, Arney L, Ojeda S, Zhang M, Keys J, Potter EL, Chu H, Moore P, Salazar MG, Iyer S, Jabara C, Kirchherr J, Mapanje C, Ngandu N, Seoighe C, Hoffman I, Gao F, Tang Y, Labranche C, Lee B, Saville A, Vermeulen M, Fiscus S, Morris L, Karim SA, Haynes BF, Shaw GM, Korber BT, Hahn BH, Cohen MS, Montefiori D, Williamson C, Swanstrom R. Comparison of the Viral Env Protein From Acute and Chronic Infections of Subtype C HIV Suggests A New Strategy For Immunogen Design. J Virol. 2013 Jul;87(13):7218-33. b. Anderson JA, Ping LH, Dibben O, Jabara CB, Arney L, Kincer L, Tang Y, Hobbs M, Hoffman I, Kazembe P, Jones CD, Borrow P, Fiscus S, Cohen MS, Swanstrom R. HIV Populations In Semen Arise Through Three Distinct Mechanisms: Direct Import from Blood, Clonal Amplification, and compartmentalization. PLoS Pathog. 2010 Aug 19; 6(8) e1001053.
5. Characterization of Cholesterol and cholesterol trafficking proteins in HIV and other retroviral replication. We have defined the role of cholesterol and cholesterol trafficking protein in HIV and other retroviruses. This work has identified role of cholesterol trafficking protein in HIV replication. a. Tang Y, George A, Taylor T, Hildreth JE. Cholesterol depletion inactivates XMRV and leads to viral envelope protein release from virions: evidence for role of cholesterol in XMRV infection. PLoS One. 2012;7(10):e48013 b. Tang Y, Leao IC, Coleman EM, Broughton RS, Hildreth JE. Deficiency of Niemann-Pick Type C-1 Protein Impairs Release of Human Immunodeficiency Virus Type 1 and Results in Gag Accumulation in Late Endosomal/Lysosomal Compartments. Journal of Virology, 2009, 83: 7982-7995.
The List of Published Work in My Bibliography: http://www.ncbi.nlm.nih.gov/myncbi/browse/collection/40065399/?sort=date&direction=descending
Research Support Active R21 AI132458 (Ruiwu Liu, PI; Yuyang Tang, Co-investigator) 8/17/2017-8/16/2019 NIH/NIAID Title: Rapid Assessment of Zika Virus (ZIKV) Complications (R21) The goal is to develop chemical intravenous-immunoglobulins (CIVIG) as an effective novel therapeutic/prophylactic antibody against Zika virus
Completed UC Davis-Fapesp Sprint Program (James E. Hildreth PI, Yuyang Tang, Co-PI; Brazil site PI, Jorge Casseb) 03/01/16-03/01/18 Title: Evaluation of HIV tropism in individuals co-infected with HTLV-I/II in Brazil The goal is to recruit HIV/HTLV co-infected and HIV alone patients from Brazil and determine the presence of HTLV Env pseudotyped HIV as a factor to enhance HIV sexual-transmission.
Pending R01 (David Margolis PI; Yuyang Tang, key-investigator) 2019-2023 NIH/NIAID Title: Incidence, risk factors and molecular mechanisms of HIV-associated neurocognitive disorder (HAND) in Brazil The goal is to evaluate HIV-associated neurocognitive disorder (HAND) incidence in Brazil and further to define risk factors and molecular basis of HAND.