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. Our laboratory research is focused on HIV envelope structure, envelope-based vaccine design and development, and other anti-HIV research approaches as 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.

Research Articles

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

2. Finzi A, Pacheco B, Xiang SH, Pancera M, Herschhorn A, Wang L, Zeng X, Desormeaux A, Kwong PD, Sodroski J. Lineage-specific Differences Between Human and Simian Immunodeficiency Virus Regulation of gp120 Trimer Association and CD4 Binding. J Virol. 2012 Sep; 86(17):8974-86.

3. Côté M, Zheng YM, Xiang SH, and Liu SL. Critical Role of a Leucine-Valine Change in the Distinct Low pH Requirements for  Membrane Fusion between Two Related Retrovirus Envelopes J Biol Chem. 2012. Mar 2; 287(10):7640-51.

4. Abudu A, Wang X, Dang Y, Zhou T, Xiang SH, Zheng YH. Identification of molecular determinants from moloney leukemia virus 10 (MOV10) protein for viron packaging and anti-human immunodefiency virus type 1(HIV-1) activity.  J Biol Chem. 2012 Jan 6; 287(2):1220-8.

5. Xiang SH, Finzi A, Pacheco B, Alexander K, Yuan W, Rizzuto C, Huang CC, Kwong PD, and Sodroski J. A V3 Loop-Dependent gp120 Element Disrupted by CD4 Binding Stabilizes the Human Immunodeficiency Virus (HIV-1) Envelope Glycoprotein Trimer. J. Virol. 84:3147-61, 2010.

6. Finzi A, Xiang SH, Pacheco B, Wang L, Haight J, Kassa A, Danek A, Pancera A, Kwong PD, and Sodroski J. Topological Layers in the HIV-1 gp120 Inner Domain Regulate gp41 Interaction and CD4-Triggered Conformational Transitions. Molecular Cell. 12:37, 656-667, 2010.

7. Kassa A, Madani N, Schön A, Haim H, Finzi A, Xiang SH, Wang L, Princiotto A, Pancera M, Courter J, Smith AB 3rd, Freire E, Kwong PD, Sodroski J. Transitions to and from the CD4-bound conformation are modulated by a single-residue change in the human immunodeficiency virus type 1 gp120 inner domain. J Virol. 83:8364-78. 2009.

8. Madani N, Schön A, Princiotto AM, Lalonde JM, Courter JR, Soeta T, Ng D, Wang L, Brower ET, Xiang SH, Kwon YD, Huang CC, Wyatt R, Kwong PD, Freire E, Smith AB 3rd, Sodroski J. Small-molecule CD4 mimics interact with a highly conserved pocket on HIV-1 gp120. Structure. 16:1689-701, 2008.

9. Pcheco B, Basmaciogullari S, Labonte JA, Xiang SH, Sodroski J. Adaptation of the human immunodeficiency virus type 1 envelope glycoproteins to new world monkey receptors. J Virol. 8:346-57, 2008.

10. Hang CC, Lam SN, Acharya P, Tang M, Xiang SH, Hussan SS, Stanfield RL, Robinson J, Sodroski J, Wilson IA, Wyatt R, Bewley CA, Kwong PD. Structures of the CCR5 N terminus and of a tyrosine-sulfated antibody with HIV-1 gp120 and CD4. Science. 317:1930-4, 2007.

7. Zhou T, Xu L, Dey B, Hessell AJ, Van Ryk D, Xiang SH, Yang X, Zhang MY, Zwick MB, Arthos J, Burton DR, Dimitrov DS, Sodroski J, Wyatt R, Nabel GJ, Kwong PD. Structural definition of a conserved neutralization epitope on HIV-1 gp120. Nature. 445:732-7, 2007.

11. Zheng G, Wang Y, Xiang SH, Tay YC, Wu H, Watson D, Coombes J, Rangan GK, Alexander SI, Harris DC. DNA vaccination with CCL2 DNA modified by the addition of an adjuvant epitope protects against "nonimmune" toxic renal injury. Journal of the American Society of Nephrology. 17: 465-74, 2006.

12. Xiang SH, Farzan M, Si Z, Madani N, Wang L, Rosenberg E, Robinson J, Sodroski J. Functional mimicry of a human immunodeficiency virus type 1 coreceptor by a neutralizing monoclonal antibody. J Virol. 79:6068-77, 2005.

13. Xiang, SH., Wang, L., Abreu, M., Rosenberg, E., Robinson, J.E., and J. Sodroski. Epitiope mapping and characterization of a novel CD4-induced human monoclonal antibody capable of neutralizing primary HIV-1 strains. Virology. 315:124-134, 2003.

14. Xiang SH, Doka N, Choudhary RK, Sodroski J, Robinson JE. Characterization of CD4-Induced Epitopes on the HIV Type 1 gp120 Envelope Glycoprotein Recognized by Neutralizing Human Monoclonal Antibodies. AIDS Res Hum Retroviruses. 18:1207-17, 2002.

15. Xiang SH, Kwong PD, Gupta R, Rizzuto CD, Casper DJ, Wyatt R, Wang L, Hendrickson WA, Doyle ML, Sodroski J. Mutagenic stabilization and/or disruption of a CD4-bound state reveals distinct conformations of the human immunodeficiency virus type 1 gp120 envelope glycoprotein. J Virol. 76:9888-99, 2002.

16. Xiang SH, Parsons HK and Murray M.  Identification of a novel transcriptional silencer in the protein-coding region of the human CYP2C9 gene.  Gene. 209:123-9, 1998.

17. Wang B, Ge YC, Palasanthiran P, Xiang SH, Ziegler J, Dwyer DE, Randle C, Dowton D, Cunningham AL and Saksena NK.  Gene defects clustered at the C-terminus of the vpr gene of HIV-1 in long-term nonprogressing mother and child pair: in vivo evolution of vpr quasispecies in blood and plasma.  Virology.223:224-32, 1996.

18. Xiang S-H, Hobbs M and Reeves PR.  Molecular analysis of the rfb gene cluster of a group D2 Salmonella enterica strain: evidence for its origin from an insertion sequence mediated recombination event between group E and D1 strains.  J Bacteriol. 14:4357-65, 1994.

Education

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