Xiao-Fang Yu, MD
Center & Institute Affiliations
MMI - Room E5148
MD, Beijing Medical University, 1990
DSc, Harvard University
One area of research in my laboratory is to understand the molecular mechanisms of HIV-1 pathogenesis. It is known that people infected with HIV-1 can have dramatically different outcomes. Some infected people develop AIDS quickly while others remain asymptomatic for years. Although the host immune response may account for the observed differences, evidence suggests that properties of HIV-1 area also responsible. Persons who acquire the virus from sick people also develop disease quickly, whereas others who acquire the virus from people who have remained healthy for years also stay healthy for 7-10 years. Recently, we have identified regions in the Env protein of HIV-1 gp120 that affect the cytopathogenicity of different HIV-1 strains. Although the viruses replicated efficiently in primary CD4+ T lymphocytes, certain viruses did not kill these cells, while others did. Experiments will be carried out to determine the mechanism of CD4+ cell killing and gp120 sequence variations. Since some of these regions of gp120 also induce neutralization antibodies, our study will generate useful information for the design of an effective HIV vaccine.
Another goal of our research is to study the mechanism of HIV assembly and entry, using biochemical, genetic, cellular and molecular biological techniques. Present studies have concentrated on the mechanism of packaging of various viral proteins (including Gag, Env and regulatory proteins) into mature HIV virions and the function of these proteins in virus entry. Genetic studies have revealed that the matrix protein and transmembrane protein are important for the incorporation of viral Env proteins into mature HIV-1 virions and for virus infectivity. Further studies will concentrate on tGag and Env protein intracellular targeting and interaction. Assembly of HIV virions requires correct targeting of viral structural proteins Gag, Pol, Env, and regulatory proteins Vpr and/or Vpx to the site of virus budding. These processes involve interactions between different viral and cellular proteins which are the fundamental issues of cell biology. Our studies will identify new targets for design of anti-HIV inhibition.
An understanding of the mechanisms by which effective cytotoxic T lymphocytes (CTL) can be elicited against internal virion proteins of HIV-1 such as Gag and Pol is essential to the development of a safe and effective HIV vaccine. This is because antibodies to these internal virion proteins will have little effect on the neutralization of HIV-1 virions. On the other hand, effective CTL response to these viral proteins will eliminate virus-infected cells, therefore preventing the spread of virus infection. To induce effective CTL responses, these viral proteins have to be Endogenously synthesized. This can be achieved by using live-attenuated virus, virus expression vector such as vaccinia, or DNA vaccines. DNA vaccines represent a novel means of expressing antigens in vivo for the generation of host immune responses, particularly CTL. Unfortunately, expression of HIV-1 Gag protein has been hampered by the stringent requirement of co-expression with other viral components, such as Rev and RRE. Furthermore, even with Rev and RRE, expression of HIV-1 Gag is negligible in Murine cells. These problems have limited our ability to address a key issue of how to generate effective CTL response to Gag using a mouse model. In order to overcome this problem, we have constructed a novel DNA expression vector and a recombinant Sindbis vector, which enables us to express Gag protein in a Rev and RRE independent and species independent fashion. More importantly, these strategies will allow us to systematically evaluate the expression of different forms of HIV-1 Gag and the immune responses against these Gag molecules in the Murine system.
- Molecular Microbiology and Immunology molecular mechanisms of HIV-1 pathogenesis HIV-1
Zhu C, Gao W, Zhao K, Qin X, Zhang Y, Peng X, Zhang L, Dong Y, Zhang W, Li P, Wei W, Gong Y, Yu XF. Structural insight into dGTP-dependent activation of tetrameric SAMHD1 deoxynucleoside triphosphate triphosphohydrolase. Nat Commun. 2013 Nov 12;4:2722. doi: 10.1038/ncomms3722.
Zhao K, Du J, Han X, Goodier JL, Li P, Zhou X, Wei W, Evans SL, Li L, Zhang W, Cheung LE, Wang G, Kazazian HH Jr, Yu XF. Modulation of LINE-1 and Alu/SVA retrotransposition by Aicardi-Goutières syndrome-related SAMHD1 Cell Rep. 2013 Sep 26;4(6):1108-15. doi: 10.1016/j.celrep.2013.08.019. Epub 2013 Sep 12.
Zhang W, Du J, Evans SL, Yu Y, Yu XF. T-cell differentiation factor CBF-β regulatesHIV-1 Vif-mediated evasion of host restriction. Nature. 2012; 481(7381):376-9. doi: 10.1038/nature10718.
Wang J, Reuschel EL, Shackelford JM, Jeang L, Shivers DK, Diehl JA, Yu XF, Finkel TH. HIV-1 Vif promotes the G1-to-S phase cell cycle transition.Blood. 2011 Jan 27;117(4):1260-9. doi: 10.1182/blood-2010-06-289215. Epub 2010 Dec 13.
Ehrlich E., Tao Wang, Kun Luo, Zuoxiang Xiao, Anna Maria Niewiadomska,
Tara Martinez, Wanping Xu, Len Neckers,and Yu XF. Regulation of Hsp90 client proteins by a Cullin5-RING E3 ubiquitin ligase. Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20330-5. Epub 2009 Nov 20.
Yu X, Yu Y, Liu B, Luo K, Kong W, Mao P, Yu XF. Induction of APOBEC3G ubiquitination and degradation by an HIV-1 Vif-Cul5-SCF complex. Science. 302 (5647):1056-60 (2003).