One of the hallmarks of HIV-1 is its high genetic variability, which is demonstrated by the large number of variants circulating in the human population. This property of HIV-1 enables the virus to escape antiviral drug and host immune pressures. Our research focuses on the evolution and adaption of HIV-1 in response to such selection pressures.
The first line of research aims to identify and characterizing cis-acting elements essential for RNA dimerization as novel antiviral targets. A number of antiviral drugs targeting different processes in the HIV replication cycle are available to control virus replication. Antivirals development has expanded to explore ways to hinder or prevent HIV-1 RNA dimerization because growing evidences have indicated that this process is essential for generating mature infectious viral particles. We seek to reveal new targets for blocking RNA dimerization that can affect the continuous replication of HIV-1 in the host. Both aminoglycoside-based and nucleic acids-based therapeutics have been used to target the major cis-acting element in the viral genome responsible for HIV-1 RNA dimerization. However, our study showed that HIV-1 without such element undergoes very rapid evolution by mutation or recombination with another strain, and regains wild type-like infectivity and pathogenicity in a very short period of time. The ever-changing nature of HIV-1 highlights the urgent need for finding more novel drug targets that prevent the replication of HIV-1. We are currently characterizing a series of cis-acting elements that affect the generation and dimerization of full-length HIV genomes. We study the adaptation of HIV-1 with mutations or deletions in these elements to delineate the escape pathways and assess the suitability of the element as antiviral target. Identifying and characterizing these cis-acting elements are important because it will provide knowledge needed to develop new strategies to curb HIV-1 replication.
A second line of research focuses on the generation and emergence of intersubtype recombinants in human. Genetic recombination is a major mechanism that generates rapid diversification of HIV-1 populations by reassorting mutations generated by reverse transcriptase. Recombination generates HIV-1 intersubtype recombinants and these recombinants now contribute significantly to the AIDS pandemic. We sought to test the hypothesis that the generation and emergence of HIV-1 intersubtype recombinant in the human population is selected by both the replication capacity of the virus and the CTL response of the host. Together with our collaborators at the Federal University of Sao Paulo, Brazil, we seek to define the correlation between disease progression rate and replication capacity of primary recombinant isolates or chimera carrying portion of the isolate in a neutral backbone. We study the function of the HIV-specific CTL response to elucidate the immune escape pathways of the recombinant and to reveal the dynamics of the duel between host and recombinant. Such information has important implications for HIV-1 vaccine development that aims at eliciting host CTL response.
Our research focuses on the evolution and adaption of HIV-1 as a way to understand the biology of HIV-1 using two different approaches. We first identify and characterize regions in the viral genome crucial for making infectious virus. We then systemically force HIV-1 to evolve and compensate for the loss of such regions essential for replication. Using this approach, we can advance our understanding of the mechanisms of HIV-1 replication as well as revealing novel targets for antiviral therapy. Another approach involves the study of recombinant HIV-1 in humans characterizing the virological properties of the virus and the immunological statuses of the host. These recombinant HIV-1 represent a selected and surviving population of HIV-1 variant. We seek to define the evolution pathways of these successful variants and delineate how they escape the host immunity. The objective of this study is to aid the development of effective HIV-1 vaccine which is hindered by the increasing prevalence of recombinant HIV-1 in the human population.
NAME:Mario Chin
POSITION TITLE: ADARC Scholar
EDUCATION
| 1998 |
B.Sc. The University of Hong Kong, Hong Kong, China |
| 2003 |
Ph.D. The University of Hong Kong |
PROFESSIONAL EXPERIENCE
| 2003-2008 |
Postdoctoral Visiting Fellow, HIV Drug resistance Program, National Cancer Institute, National Institutes of Health, Frederick, MD. |
| 2008-present |
Aaron Diamond Scholar, Aaron Diamond AIDS Research Center, New York, NY |
AWARDS
| 2007 |
International AIDS Society International Scholarship |
| 2007 |
Fellows Award for Research Excellence, National Institutes of Health |
| 2006 |
Fellows Award for Research Excellence, National Institutes of Health |
| 1999-2000 |
Swire Scholarship, The University of Hong Kong |
PRPFESSIONAL SOCIETIES
International AIDS Society
American Society of Virology
PUBLICATIONS (SELECTED)
- Hoffmann E., J. Stech, I. Leneva, S. Krauss, C. Scholtissek, P.S. Chin, M. Peiris, K.F. Shortridge and R.G. Webster. (2000) Characterization of the influenza A virus gene pool in avian species in southern China: was H6N1 a derivative or a precursor of H5N1? Journal of Virology 74:6309-6315.
- Guan Y., K.F. Shortridge, S. Krauss, P.S. Chin,K.C. Dyrting, T.M. Ellis, R.G. Webster and M. Peiris. (2000) H9N2 influenza viruses possessing H5N1-like internal genomes continue to circulate in poultry in southeastern China. Journal of Virology 74:9372-9380.
- P.S. Chin,E. Hoffmann, R. Webby, R.G. Webster, Y. Guan, M. Peiris and K.F. Shortridge. (2002) Molecular evolution of H6 influenza viruses from poultry in southeastern China: prevalence of H6N1 influenza viruses possessing seven A/HK/156/97 (H5N1)-like genes in poultry. Journal of Virology. 76:507-516.
- Webby R.J., P.R. Woolcock, S.L. Krauss, D.B. Walker, P.S. Chin, K.F. Shortridge and R.G. Webster. (2003) Multiple genotypes of non-pathogenic H6N2 influenza viruses isolated from chickens in California. Avian Disease. 47:905-910.
- P.S. Chin,T.D. Rhodes, J. Chen, W. Fu and W.S. Hu (2005) Identification of a major restriction in HIV-1 intersubtype recombination. Proc. Natl. Acad. Sci. U.S.A. 102:9002-9007.
- P.S. Chin,J. Chen, O.A. Nikolaitchik and W.S. Hu. (2007) Molecular determinants of HIV-1 intersubtype recombination potential. Virology 363:437-446.
- P.S. Chin, S.K. Lee , J. Chen, O.A. Nikolaitchik, D. Powell, M.J. Fivash Jr. and W.S. Hu. (2008) Long-range recombination gradient between HIV-1 subtypes B and C variants caused by sequence differences in the dimerization initiation signal region. Journal of Molecular Biology 377:1324-1333.
BOOK CHAPTERS:
- Guan Y., K.F. Shortridge, S. Krauss, P.S. Chin, K.C. Dyrting, T.M. Ellis, R.G. Webster and M. Peiris. (2001) Two lineages of H9N2 influenza viruses continue to circulate in land-based poultry in southeastern China. In Osterhaus, A.D.M.E., Cox, N.J. and Hampson, A.W. (eds.) Options for the Control of Influenza IV. Elsevier Science B.V., Amsterdam, The Netherlands. pp. 187-193.
- Moore, M.D., M.P.S. Chin and W.S. Hu. (2009) HIV-1 recombination: An experimental assay and a phylogenetic approach. In Prasad V. and Kalpana G. (eds.) HIV Protocols. Second Edition. Humana Press, Inc., New Jersey, U.S.A. pp. 87-105
- Hoffmann E., J. Stech, I. Leneva, S. Krauss, C. Scholtissek, P.S. Chin, M. Peiris, K.F. Shortridge and R.G. Webster. (2000) Characterization of the influenza A virus gene pool in avian species in southern China: was H6N1 a derivative or a precursor of H5N1? Journal of Virology 74:6309-6315. [view]
- Hoffmann E., J. Stech, I. Leneva, S. Krauss, C. Scholtissek, P.S. Chin, M. Peiris, K.F. Shortridge and R.G. Webster. (2000) Characterization of the influenza A virus gene pool in avian species in southern China: was H6N1 a derivative or a precursor of H5N1? Journal of Virology 74:6309-6315.
- Guan Y., K.F. Shortridge, S. Krauss, P.S. Chin,K.C. Dyrting, T.M. Ellis, R.G. Webster and M. Peiris. (2000) H9N2 influenza viruses possessing H5N1-like internal genomes continue to circulate in poultry in southeastern China. Journal of Virology 74:9372-9380.
- P.S. Chin,E. Hoffmann, R. Webby, R.G. Webster, Y. Guan, M. Peiris and K.F. Shortridge. (2002) Molecular evolution of H6 influenza viruses from poultry in southeastern China: prevalence of H6N1 influenza viruses possessing seven A/HK/156/97 (H5N1)-like genes in poultry. Journal of Virology. 76:507-516.
- Webby R.J., P.R. Woolcock, S.L. Krauss, D.B. Walker, P.S. Chin, K.F. Shortridge and R.G. Webster. (2003) Multiple genotypes of non-pathogenic H6N2 influenza viruses isolated from chickens in California. Avian Disease. 47:905-910.
- P.S. Chin,T.D. Rhodes, J. Chen, W. Fu and W.S. Hu (2005) Identification of a major restriction in HIV-1 intersubtype recombination. Proc. Natl. Acad. Sci. U.S.A. 102:9002-9007.
- P.S. Chin,J. Chen, O.A. Nikolaitchik and W.S. Hu. (2007) Molecular determinants of HIV-1 intersubtype recombination potential. Virology 363:437-446.
- P.S. Chin, S.K. Lee , J. Chen, O.A. Nikolaitchik, D. Powell, M.J. Fivash Jr. and W.S. Hu. (2008) Long-range recombination gradient between HIV-1 subtypes B and C variants caused by sequence differences in the dimerization initiation signal region. Journal of Molecular Biology 377:1324-1333. , equal contribution (PMID: 18314135)
| Mario Chin |
ADARC Scholar |
| Natalia Ristic |
Research Technician |
Mario Chin, Ph.D. 
Masahiro Yamashita, Ph.D.