Dr. Hengli Tang
|Office: ||3063 King Life Sciences
|Office: ||(850) 645-2402
|Lab: ||King Life Sciences
|Lab: ||(850) 645-2403
|Fax: ||(850) 645-8447
|Mail code: ||4295|
Ph.D., University of California, San Diego, 1998
Graduate Faculty Status
Research and Professional Interests:
The general area of research interest in my lab is virus-host cell interactions concerning hepatitis C virus (HCV) and flaviviruses such as dengue (DENV) and Zika viruses (ZIKV). We are currently using pluripotent stem cells and targeted differentiation in vitro to study viral susceptibility of cells from distinct lineages.
1. Stem cell differentiation and positive-strand RNA viruses
Pluripotent stem cells can be differentiated into all cell lineages in vitro, providing distinct cell types with identifical genetic background for studies of virus susceptiblity. In addition, the tightly controlled nature of the in vitro differentiation steps is also well-suited for identifying the transition to virus permissiveness during differentiation. We have previously published hepatic differentiation and HCV infection (Wu et al. PLoS Pathogens 2012) and are currently using additional differentiated cells for the studies of dengue virus and Zika virus.
Recent papers on Zika virus:
Recent paper on Dengue virus:
2. Cellular cofactors of viral infection
My lab has characterized two cellular cofactors essential for HCV infection. We investigated in depth the relationship between Cyclophilin A (CyPA), a host factor, and HCV infection in vitro. HCV infection of cultured hepatoma cells or differentiated hepatocyte-like cells derived from stem cells is critically dependent on CyPA but not several other isoforms of CyPs. The peptidylprolyl isomerase (PPIase) motif of CyPA is essential for the function of the HCV replicase. In vitro resistance to CsA, albeit modest, is directly correlated with a reduced dependence on CyPA; and a functional interaction between CyPA and the HCV replicase exists. NS5A, a HCV non-structural protein and a component of the viral replicase, is an important target of CyPA. Mutations that alter NS5A conformation reduce HCV's dependence on CyPA. The second cellular cofactor, CIDEB, is not only important for HCV infection but may also play a role in HCV-mediated lipid dysregulation.
3. Cofactor-Independent Mutants (CoFIM) selection
A myriad of cellular cofactors have been identified by various labs using shot-gun style technologies such as siRNA screening (genome-wide or targeted) and cDNA expression cloning. However, the mechanisms of action for many of these factors remain unknown. We have devised a Cofactor-Independent Mutants (CoFIM) identification technique (Yang et al. PLoS Pathogens, 2010) to select for mutations that confer the ability to a mutant virus that can infect cells where the expression of a specific cofactor is suppressed by stable shRNA. This approach allows us to identify the viral targets and the mutations relevant for the function of given cofactors. We have validated this technology with CyPA, an essential cofactor of HCV that has been well characterized by us and others. We are now applying the CoFIM technique to additional HCV and HIV cofactors.
Xu, M., Lee, EM.,Wen, Z., Cheng, Y., Huang, W., Qian, X., TCW, J., Kouznetsova, J., Ogden., SC., Hammack, C., Jacob, F., Nguyen, HN., Itkin, M., Hanna, C., Shinn, P., Allen, C., Michael, SG., Simeonov, A., Huang, W., Christian, KM., Goate, A., Brennand, KJ., Huang, R., Xia, M., Ming, G., Zheng, W., Song, H., Tang, H. 2016 Aug 22. Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Nature Medicine. doi:10.1038/nm.4184
Zhang, F., Hammack, C., Ogden, S. C., Cheng, Y., Lee, E. M., Wen, Z., Qian, X., Nguyen, H., Li ,Y., Yao, B., Xu, M., Xu, T., Chen, L., Wang, Z., Feng, H., Huang, W., Yoon, K., Shan, C., Huang, L., Qin, Z., Christian, K M., Shi, P., Xu, M., Xia, M., Zheng, W., Wu, H., Song, H., Tang, H., Ming, G., Jin, P. 2016 Aug 31. Molecular signatures associated with ZIKV exposure in human cortical neural progenitors. Nucleic Acids Research, doi:10.1093/nar/gkw765
Lang, J., Vera, D., Cheng, Y., & Tang, H. 2016 Aug 16. Modeling dengue virus-hepatic cell interactions using human pluripotent stem cell-derived hepatocyte-like cells. Stem Cell Reports, doi:http://dx.doi.org/10.1016/j.stemcr.2016.07.012
Qian, X., Ha Nam Nguyen, Song, M. M., Hadiono, C., Ogden, S. C., Hammack, C., Yao, B., Hamersky, GR., Jacob, F., Zhong, C., Yoon, KJ., Jeang, W., Lin, L., Li, YJ., Thakor, J., Berg, DA., Zhang, C., Kang, E., Chickering, M., Nauen, D., Ho, CY., Wen, ZX., Christian, KM., Shi, PY., Maher, BJ., Wu, H., Jin, P., Tang, HL., Song, HJ., Ming, G. 2016 May 19. Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell, 165(5), 1238-1254. doi:10.1016/j.cell.2016.04.032
Tang H, Hammack C, Ogden SC, Wen Z, Qian X, Li Y, Yao B, Shin J, Zhang F, Lee EM, Christian KM, Didier RA, Jin P, Song H, Ming GL. Zika Virus Infects Human Cortical Neural Progenitors and Attenuates Their Growth. Cell Stem Cell. 2016 Mar 3. pii: S1934-5909(16)00106-5. doi: 10.1016/j.stem.2016.02.016. [Epub ahead of print]
Lee EM, Alsagheir A, Wu X, Hammack C, McLauchlan J, Watanabe N, Wakita T, Kneteman NM, Douglas DN, Tang H. Hepatitis C virus induced degradation of cell death-inducing DFFA-like effector B leads to hepatic lipid dysregulation. J Virol. 2016 Feb 10. pii: JVI.02891-15. [Epub ahead of print]
Hookway TA, Butts JC, Lee E, Tang H, McDevitt TC. Aggregate formation and suspension culture of human pluripotent stem cells and differentiated progeny. Methods. 2015 Dec 2. pii: S1046-2023(15)30167-5. doi: 10.1016/j.ymeth.2015.11.027. [Epub ahead of print]
Ogden SC, Tang H. The missing pieces of the HCV entry puzzle. Future Virol. 2015;10(4):415-428.
Lee T, Di Paola D, Malina A, Mills JR, Kreps A, Grosse F, Tang H, Zannis-Hadjopoulos M, Larsson O, Pelletier J. Suppression of the DHX9 helicase induces premature senescence in human diploid fibroblasts in a p53-dependent manner. J Biol Chem. 2014 Aug 15;289(33):22798-814. doi: 10.1074/jbc.M114.568535. Epub 2014 Jul 2.
Wu X, Lee EM, Hammack C, Robotham JM, Basu M, Lang J, Brinton MA, Tang H. Cell death-inducing DFFA-like effector b is required for hepatitis C virus entry into hepatocytes. J Virol. 2014 Aug;88(15):8433-44. doi: 10.1128/JVI.00081-14. Epub 2014 May 14
Yu F, Peng Y, Wang Q, Shi Y, Si L, Wang H, Zheng Y, Lee E, Xiao S, Yu M, Li Y, Zhang C, Tang H, Wang C, Zhang L, Zhou D. Development of bivalent oleanane-type triterpenes as potent HCV entry inhibitors. Eur J Med Chem. 2014 Apr 22;77:258-68. doi: 10.1016/j.ejmech.2014.03.017. Epub 2014 Mar 7.
Che P, Tang H, Li Q. The interaction between claudin-1 and dengue viral prM/M protein for its entry. Virology. 2013 Nov;446(1-2):303-13. doi: 10.1016/j.virol.2013.08.009. Epub 2013 Sep 7.
Frausto SD, Lee E, Tang H. Cyclophilins as modulators of viral replication.Viruses. 2013 Jul 11;5(7):1684-701. doi: 10.3390/v5071684. Review.
Jiang J, Wu X, Tang H, Luo G. Apolipoprotein E mediates attachment of clinical hepatitis C virus to hepatocytes by binding to cell surface heparan sulfate proteoglycan receptors. PLoS One. 2013 Jul 2;8(7):e67982. doi: 10.1371/journal.pone.0067982. Print 2013.
- Wu X, Robotham JM, Lee E, Dalton S, Kneteman NM, Gilbert DM, Tang H. Productive Hepatitis C Virus Infection of Stem Cell-Derived Hepatocytes Reveals a Critical Transition to Viral Permissiveness during Differentiation. PLoS Pathog. 2012 Apr;8(4):e1002617. Epub 2012 Apr 5.
- Nag A, Robotham JM, Tang H. Suppression of Viral RNA Binding and the Assembly of Infectious Hepatitis C Virus Particles in vitro by Cyclophilin Inhibitors. J Virol. 2012 Sep 12. [Epub ahead of print]
- Grisé H, Frausto S, Logan T, Tang H. A Conserved Tandem Cyclophilin-Binding Site in Hepatitis C Virus Nonstructural Protein 5A Regulates Alisporivir Susceptibility. J Virol. 2012 May;86(9):4811-22. Epub 2012 Feb 15.
- Jiang J, Cun W, Wu X, Shi Q, Tang H, Luo G. Hepatitis C virus attachment mediated by apolipoprotein E binding to cell surface heparan sulfate. J Virol. 2012 Jul;86(13):7256-67. Epub 2012 Apr 24
- Hebner CM, Han B, Brendza KM, Nash M, Sulfab M, Tian Y, Hung M, Fung W, Vivian RW, Trenkle J, Taylor J, Bjornson K, Bondy S, Liu X, Link J, Neyts J, Sakowicz R, Zhong W, Tang H, Schmitz U. The HCV non-nucleoside inhibitor Tegobuvir utilizes a novel mechanism of action to inhibit NS5B polymerase function. PLoS One. 2012;7(6):e39163. Epub 2012 Jun 13.
- Yang F, Robotham JM, Grise H, Frausto S, Madan V, et al. (2010) A Major Determinant of Cyclophilin Dependence and Cyclosporine Susceptibility of Hepatitis C Virus Identified by a Genetic Approach. PLoS Pathog 6(9): e1001118. doi:10.1371
- Tang H. Cyclophilin Inhibitors as a Novel HCV Therapy. Viruses. 2010; 2(8):1621-1634.
- Tang H, Grisé H. Cellular and molecular biology of HCV infection and hepatitis. Clin Sci (Lond). 2009 Jun 15;117(2):49-65.
- Kenworthy R, Lambert D, Yang F, Wang N, Chen Z, Zhu H, Zhu F, Liu C, Li K, Tang H. Short-hairpin RNAs delivered by lentiviral vector transduction trigger RIG-I-mediated IFN activation. Nucleic Acids Res. 2009 Oct;37(19):6587-99. Epub 2009 Sep 3.
- Liu Z, Robida JM, Chinnaswamy S, Yi G, Robotham JM, Nelson HB, Irsigler A, Kao CC, Tang H. Mutations in the hepatitis C virus polymerase that increase RNA binding can confer resistance to cyclosporine A. Hepatology. 2009 Jul;50(1):25-33.
- Liu Z, Yang F, Robotham JM, Tang H. Critical role of cyclophilin A and its prolyl-peptidyl isomerase activity in the structure and function of the hepatitis C virus replication complex. J Virol. 2009 Jul;83(13):6554-65. Epub 2009 Apr 22.
- Robotham JM, Nelson HB, Tang H. Selection and characterization of drug-resistant HCV replicons in vitro with a flow cytometry-based assay. Methods Mol Biol. 2009;510:227-42.
- Qing M, Yang F, Zhang B, Zou G, Robida JM, Yuan Z, Tang H, Shi PY. Cyclosporine inhibits flavivirus replication through blocking the interaction between host cyclophilins and viral NS5 protein. Antimicrob Agents Chemother. 2009 Aug;53(8):3226-35. Epub 2009 May 18.
- Yang F, Robotham JM, Nelson HB, Irsigler A, Kenworthy R, Tang H. Cyclophilin A is an Essential Cofactor for Hepatitis C Virus Infection and the Principal Mediator of Cyclosporine A Resistance In Vitro. J Virol. 2008 Apr 2; [Epub ahead of print]
- Liu Z, Kenworthy R, Green C, Tang H. Molecular determinants of nucleolar translocation of RNA helicase A. Exp Cell Res. 2007 Oct 15;313(17):3743-54. Epub 2007 Aug 14.
- Robida JM, Nelson HB, Liu Z, Tang H. Characterization of Hepatitis C Virus Subgenomic Replicon Resistance to Cyclosporine A In Vitro. J Virol. 2007 Mar 21; [epub ahead of print]
- Nelson HB, Tang H. Effect of cell growth on hepatitis C virus (HCV) replication and a mechanism of cell confluence-based inhibition of HCV RNA and protein expression. J Virol. 2006 Feb;80(3):1181-90.
- Waninger S, Kuhen K, Hu X, Chatterton JE, Wong-Staal F, Tang H. Identification of cellular cofactors for human immunodeficiency virus replication via a ribozyme-based genomics approach. J Virol. 2004 78(23):12829-12837.
- Tang H, Peng T, Wong-Staal F. Novel technologies for studying virus-host interaction and discovering new drug targets for HCV and HIV. Curr Opin Pharmacol. 2002 2(5):541-7.
- Kuwabara T, Warashina M, Sano M, Tang H, Wong-Staal F, Munekata E, Taira K. Recognition of engineered tRNAs with an extended 3' end by Exportin-t (Xpo-t) and transport of tRNA-attached ribozymes to the cytoplasm in somatic cells. Biomacromolecules. 2001 2(4):1229-42.
- Yang JP, Tang H, Reddy TR, Wong-Staal F. Mapping the functional domains of HAP95, a protein that binds RNA helicase A and activates the constitutive transport element of type D retroviruses. J Biol Chem. 2001 276(33):30694-700.
- Reddy TR, Tang H, Xu W, Wong-Staal F. Sam68, RNA helicase A and Tap cooperate in the post-transcriptional regulation of human immunodeficiency virus and type D retroviral mRNA. Oncogene. 2000 19(32):3570-5.
- Tang H, Wong-Staal F. Specific interaction between RNA helicase A and Tap, two cellular proteins that bind to the constitutive transport element of type D retrovirus. J Biol Chem. 2000 275(42):32694-700.
- Westberg C, Yang JP, Tang H, Reddy TR, Wong-Staal F. A novel shuttle protein binds to RNA helicase A and activates the retroviral constitutive transport element. J Biol Chem. 2000 275(28):21396-401.
- Tang H, Kuhen KL, Wong-Staal F. Lentivirus replication and regulation. Annu Rev Genet. 1999;33:133-70.
- Reddy TR, Xu W, Mau JK, Goodwin CD, Suhasini M, Tang H, Frimpong K, Rose DW, Wong-Staal F. Inhibition of HIV replication by dominant negative mutants of Sam68, a functional homolog of HIV-1 Rev. Nat Med. 1999 5(6):635-42.
- Tang H, McDonald D, Middlesworth T, Hope TJ, Wong-Staal F. The carboxyl terminus of RNA helicase A contains a bidirectional nuclear transport domain. Mol Cell Biol. 1999 19(5):3540-50.
- Li J, Tang H, Mullen TM, Westberg C, Reddy TR, Rose DW, Wong-Staal F. A role for RNA helicase A in post-transcriptional regulation of HIV type 1. Proc Natl Acad Sci U S A. 1999 96(2):709-14.
- Reddy TR, Tang H, Li X, Wong-Staal F. Functional interaction of the HTLV-1 transactivator Tax with activating transcription factor-4 (ATF4). Oncogene. 1997 14(23):2785-92.
- Tang H, Gaietta GM, Fischer WH, Ellisman MH, Wong-Staal F. A cellular cofactor for the constitutive transport element of type D retrovirus. Science. 1997 276(5317):1412-5.
- Tang H, Xu Y, Wong-Staal F. Identification and purification of cellular proteins that specifically interact with the RNA constitutive transport elements from retrovirus D. Virology. 1997 Feb 17;228(2):333-9.
Robotham, Jason Michael