Shi-hua Xiang, Ph.D.

Associate Professor
Nebraska Center for Virology
School of Veterinary Medicine and Biomedical Sciences
University of Nebraska – Lincoln
4240 Fair Street, Morrison Center
Lincoln, NE 68583-0900
Phone: (402) 472-4559
Fax: (402) 472-3323
Email: sxiang2@unl.edu

Research Interests

Research Interests

Human immunodeficiency virus type 1 (HIV-1) is the etiologic agent of AIDS (Acquired Immune Deficiency Syndrome).  About thirty years after identification of HIV as the causative agent of AIDS, the AIDS epidemic remains a global health issue.  Our research interests are focused on HIV/AIDS, with the ultimate goal of developing an effective vaccine or a long-term preventive strategy to counter this devastating pandemic.  In addition, we are also working on small ruminant lentviruses (SRLV) and try to find the genetic resistant-forms against SRLV infection.  The current major projects in our laboratory are described below. 

I. Envelope Structure and Viral Entry

HIV-1 is an enveloped virus, requiring for cell entry a membrane fusion process mediated by the interactions of viral envelope glycoproteins (gp120 and gp41), a primary receptor CD4, and a chemokine coreceptor (CCR5 or CXCR4). Viral entry is a critical step for establishing infection, thus providing a powerful incentive to understand the intricate biochemical mechanisms of viral entry as a prerequisite for developing effective antiviral therapies. The interaction of HIV-1 gp120 and the CD4 receptor has been well characterized. However, the interactions between viral envelope glycoproteins and the HIV co-receptor (CCR5 or CXCR4) are poorly understood. For example, it is not clear how the HIV gp120 core and V3 loop contact the N-terminal and extracellular loops of CCR5 to facilitate the entry process, nor has the molecular structure of CCR5 been elucidated. We will investigate the interactions between gp120 and the coreceptor CCR5 or CXCR4, employing various molecular and cellular approaches to dissect these associations in more detail.

II. Envelope-Based AIDS Vaccine Development

The HIV-1 envelope has evolved such an immunosuppressive state that does not provoke adequate immunogenicity to trigger the production of neutralizing antibodies. Therefore, our research objective is to improve the immunogenicity of the HIV-1 envelope. The approach involves stabilizing a CD4-bound conformation of gp120, in which CD4 as well as the co-receptor (CCR5 or CXCR4) binding sites are exposed. These two sites are the most conserved regions in the HIV-1 Env. This gp120 antigenic conformation should induce a much stronger immune response, and consequently elicit more potent neutralizing antibodies.

Another approach involves epitope-based antigen design. Epitope information gleaned from studies of known neutralizing antibodies such as VRC01, b12 or 2G12 should facilitate fragment structure-based design. We anticipate that a small epitope might elicit potent neutralizing antibodies against the virus.

III. Commensal Bacteria for HIV Infection and Transmission Control

Mucosal surfaces in the human gastrointestinal (GI) tract (e.g. rectum) and the female genital tract (e.g. vagina) are principal sites of HIV-1 infection. Large quantities of commensal bacteria, the so-called microbiota or microflora, naturally reside on these mucosal surfaces, in mutual relationships with the human body. We will use these bacteria as a surrogate “shield” to combat HIV-1 infection and transmission. An ability to genetically engineer these bacteria so that anti-HIV molecules or antibodies can be generated on the cell surface is a unique attribute of these bacteria. Potentially infectious viral particles would be captured, immobilized, and inactivated by the engineered inhibitors on the bacterial cell surface. Since commensal bacteria colonize mucosal surfaces and replicate, a durable protection can be achieved. Thus, this approach could become a long-term strategy for prevention of HIV transmission.

IV.  Small ruminant lentviruses study

Small ruminant lentiviruses (SRLV) belong to retroviruses, like HIV.  SRLV is consisting of visna/maedi virus (VMV), ovine progressive pneumonia virus (OPPV), caprine arthritis encephalitis virus (CAEV).  They are supposed to be the same kind of viruses as they are similar in their genomic sequence similarity and also they all can infect both sheep and goats.  SRLV infection can causes multi-organ diseases, such as the lungs, brain, spinal cord, mammary glands, and the joints.  Our research is focusing on the virus-host interactions.  We are searching for the cellular receptors for viral entry, and also for the restriction factors that resist to viral infection.  The ultimate goal of this study is to find the genetic resistant-forms to SRLV infection. 




Research Articles

Persistence of SIV in the brain of SIV-infected Chinese rhesus macaques with or without antiretroviral therapy. Perez S, Johnson AM, Xiang SH, Li J, Foley BT, Doyle-Meyers L, Panganiban A, Kaur A, Veazey RS, Wu Y, Ling B., J Neurovirol. 2017 Nov 27. doi: 10.1007/s13365-017-0594-0.

Zika Virus Encoding Non-Glycosylated Envelope Protein is Attenuated and Defective in Neuroinvasion. Annamalai AS, Pattnaik A, Sahoo BR, Muthukrishnan E, Natarajan SK, Steffen D, Vu HLX, Delhon G, Osorio FA, Petro TM, Xiang SH, Pattnaik AK. J Virol. 2017 Sep 20. pii: JVI.01348-17. doi: 10.1128/JVI.01348-17.

Tryptophan 375 stabilizes the outer-domain core of gp120 for HIV vaccine immunogen design. Hu D, Bowder D, Wei W, Thompson J, Wilson MA, Xiang SH. Vaccine. 2017 May 25;35(23):3067-3075. doi: 10.1016/j.vaccine.2017.04.054. Epub 2017 Apr 29.

Mechanistic understanding of N-glycosylation in Ebola virus glycoprotein maturation and function. Wang B, Wang Y, Frabutt DA, Zhang X, Yao X, Hu D, Zhang Z, Liu C, Zheng S, Xiang SH, Zheng YH. J Biol Chem. 2017 Apr 7;292(14):5860-5870. doi: 10.1074/jbc.M116.768168. Epub 2017 Feb 14.

Lineage-Specific Differences between the gp120 Inner Domain Layer 3 of Human Immunodeficiency Virus and That of Simian Immunodeficiency Virus. Ding S, Medjahed H, Prévost J, Coutu M, Xiang SH, Finzi A. J Virol. 2016 Oct 28;90(22):10065-10073. Print 2016 Nov 15.

Sulfotyrosine dipeptide: Synthesis and evaluation as HIV-entry inhibitor. Ju T, Hu D, Xiang SH, Guo J. Bioorg Chem. 2016 Oct;68:105-11. doi: 10.1016/j.bioorg.2016.07.012. Epub 2016 Jul 25.

A Highly Conserved gp120 Inner Domain Residue Modulates Env Conformation and Trimer Stability. Ding S, Tolbert WD, Prévost J, Pacheco B, Coutu M, Debbeche O, Xiang SH, Pazgier M, Finzi A. J Virol. 2016 Sep 12;90(19):8395-409. doi: 10.1128/JVI.01068-16. Print 2016 Oct 1.

Genome-Wide Search for Host Association Factors during Ovine Progressive Pneumonia Virus Infection. Thompson J, Ma F, Quinn M, Xiang SH. PLoS One. 2016 Mar 7;11(3):e0150344. doi: 10.1371/journal.pone.0150344. eCollection 2016.

From crystal structure of α-conotoxin GIC in complex with Ac-AChBP to molecular determinants of its high selectivity for α3β2 nAChR. Lin B, Xu M, Zhu X, Wu Y, Liu X, Zhangsun D, Hu Y, Xiang SH, Kasheverov IE, Tsetlin VI, Wang X, Luo S. Sci Rep. 2016 Mar 1;6:22349. doi: 10.1038/srep22349.

Escherichia coli surface display of single-chain antibody VRC01 against HIV-1 infection. Wang LX, Mellon M, Bowder D, Quinn M, Shea D, Wood C, Xiang SH. Virology. 2015 Jan 15;475:179-86. doi: 10.1016/j.virol.2014.11.018. Epub 2014 Dec 5.

Sumoylation differentially regulates Sp1 to control cell differentiation. Gong L, Ji WK, Hu XH, Hu WF, Tang XC, Huang ZX, Li L, Liu M, Xiang SH, Wu E, Woodward Z, Liu YZ, Nguyen QD, Li DW. Proc Natl Acad Sci U S A. 2014 Apr 15;111(15):5574-9. doi: 10.1073/pnas.1315034111. Epub 2014 Mar 27.

Recent advances on the use of structural biology for the design of novel envelope immunogens of HIV-1. Xiang SH. Curr HIV Res. 2013 Sep;11(6):464-72.

A twin-cysteine motif in the V2 region of gp120 is associated with SIV envelope trimer stabilization. Bohl C, Bowder D, Thompson J, Abrahamyan L, Gonzalez-Ramirez S, Mao Y, Sodroski J, Wood C, Xiang SH. PLoS One. 2013 Jul 23;8(7):e69406. doi: 10.1371/journal.pone.0069406. Print 2013.

Molecular architecture of the uncleaved HIV-1 envelope glycoprotein trimer. Mao Y, Wang L, Gu C, Herschhorn A, Désormeaux A, Finzi A, Xiang SH, Sodroski JG. Proc Natl Acad Sci U S A. 2013 Jul 23;110(30):12438-43. doi: 10.1073/pnas.1307382110. Epub 2013 Jun 11.

Characterization of a dual-tropic human immunodeficiency virus (HIV-1) strain derived from the prototypical X4 isolate HXBc2. Xiang SH, Pacheco B, Bowder D, Yuan W, Sodroski J. Virology. 2013 Mar 30;438(1):5-13. doi: 10.1016/j.virol.2013.01.002. Epub 2013 Jan 29.

The highly conserved layer-3 component of the HIV-1 gp120 inner domain is critical for CD4-required conformational transitions. Désormeaux A, Coutu M, Medjahed H, Pacheco B, Herschhorn A, Gu C, Xiang SH, Mao Y, Sodroski J, Finzi A. J Virol. 2013 Mar;87(5):2549-62. doi: 10.1128/JVI.03104-12. Epub 2012 Dec 19.

Subunit organization of the membrane-bound HIV-1 envelope glycoprotein trimer. Mao Y, Wang L, Gu C, Herschhorn A, Xiang SH, Haim H, Yang X, Sodroski J. Nat Struct Mol Biol. 2012 Sep;19(9):893-9. doi: 10.1038/nsmb.2351. Epub 2012 Aug 5.

Lineage-specific differences between human and simian immunodeficiency virus regulation of gp120 trimer association and CD4 binding. Finzi A, Pacheco B, Xiang SH, Pancera M, Herschhorn A, Wang L, Zeng X, Desormeaux A, Kwong PD, Sodroski J. J Virol. 2012 Sep;86(17):8974-86. doi: 10.1128/JVI.01076-12. Epub 2012 Jun 13.




Education

Postdoctoral   Harvard Medical School, Boston, MA


Ph.D.   1995, Microbiology, University of Sydney, Sydney, Australia.


M.S.    1986, Mycology, Huazhong Agaricultural University, Wuhan, China.


B.S. 1982, Biology, Hunan Normal University, Changsha, China




Professional Positions

Assistant Professor - University of Nebraska-Lincoln, School of Veterinary Medicine and Biomedical Sciences, 2011 - present

Research Associate Professor – 2011, University of Nebraska – Lincoln
Nebraska Center for Virology, School of Biological Sciences

Instructor, 2004-2010, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Research Fellow, 1998-2004, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Research Officer, 1994-1997, Westmead Hospital, University of Sydney, Australia.




Honors & Awards

Grand Challenges Explorations (GCE) Awards, Phase I (2008) & Phase II (2011), Bill & Melinda Gates Foundation.

CJ Martin Fellowship Award, 1997, Australian National Health and Medical Research Council (NH&MRC).




Professional Affiliations

NCV Membership 2011 - present

American Society for Microbiology

American Society for Biochemistry and Molecular Biology

New England Structural Biology Association