Jason Kimata, Ph.D.
Department of Molecular Virology & Microbiology
Ph.D. Washington University
Postdoc, University of Washington
Pathogenicity and fitness of HIV-1 and SIV variants
Our long-term goals are to understand how HIV exploits, disrupts, and evades the immune response for replication and persistence in the host. We investigate whether the properties of the infecting HIV strain influence viral burden and disease progression. How does genetic variation in the virus influence infection, replication, persistence, and disease? What host factors drive the selection of variant viruses? Because there is currently no model system to directly explore questions about HIV-1 pathogenesis in vivo, we are using the SIV macaque model in our work. A unique set of SIV variants cloned from different stages of infection and disease provide the basis for these studies. Using these viruses, we have shown that variant viruses emerging during the course of infection influence viral load and the rate of disease progression. We are dissecting the pathogenic determinants of SIV variants and determining the functional changes that correlate with increased or decreased replicative fitness in the host in order to better understand how the virus counteracts and evades the host immune response. These studies complement other collaborative studies of HIV-1 and viral burden.
Cross-species transmission and HIV-1 animal model development
HIV-1 is the primary virus world-wide causing AIDS. However, because HIV-1 tropism is specific for humans, it has been difficult to develop an animal model of infection and disease. Nonhuman primates are not typically susceptible to infection by HIV-1, but a rare exception is the pig-tailed macaque, which can have an acute infection before clearing the virus. We recently found that unlike the rhesus macaque, the primary macaque used for SIV-AIDS studies, the pigtailed macaque is susceptible to HIV-1 infection mainly because it does not express a key intrinsic retroviral resistance factor, TRIM5a. Furthermore, we have recently developed a novel HIV-1/SIV chimera that is 94% HIV-1 and able to replicate in CD4+ T-cells from pig-tailed macaques nearly as well as SIV. This chimera also persistently replicates in pig-tailed macaques. Current studies are evaluating adaptations in the virus and if it will cause disease in the host. These studies should deepen our understanding of HIV-1 transmission and pathogenesis. Ultimately, this model may enable preclinical testing of novel antiretroviral therapies and vaccines. It can also be applied to studies of viral latency and curative treatment strategies.
Xenotropic murine leukemia virus-related virus
We are examining the link between a newly identified human gammaretrovirus called xenotropic murine leukemia virus-related virus (XMRV) and prostate cancer. In recent studies, we have found that a significant percentage of men with prostate cancer in the southern US are infected with XMRV. We are addressing the effect XMRV infection has on cell growth and proliferation of prostate epithelial cells. We are also engaged in collaborative studies examining the prevalence of XMRV in different populations and associations with disease.
Biesinger T, R White, MT Yu Kimata, BK Wilson, JS Allan, and JT Kimata. Relative replication capacity of phenotypic SIV variants during primary infections differs with route of inoculation. Retrovirology7:88 (2010).
Danielson BP, GE Ayala, and JT Kimata. Detection of XMRV in normal and tumor tissue of prostate cancer patients from the Southern United States is dependent on specific PCR conditions. J Infect Dis202:1470-1477 (2010).
Arora R, R Thippeshappa, L Bull, E Siwak, RC Arduino, and JT Kimata. Dendritic cell-mediated HIV-1 infection of T-cells demonstrates a direct relationship to plasma viral RNA levels. J Acquir Immune Defic Syndr54:115-121 (2010).
Biesinger T, MT Yu Kimata, and JT Kimata. Changes in simian immunodeficiency virus reverse transcriptase alleles that appear during infection of macaques enhance infectivity and replication in CD4+ T-cells. Virology 370:184-193 (2008).
Ambrose Z, S Palmer, VF Boltz, M Kearney, K Larson, P Polacino, L Flanary, K Oswald, M Piatak, Jr, J Smedley, W Shao, N Bischofberger, F Maldarelli, JT Kimata, JW Mellors, SL Hu, JM Coffin, JD Lifson, and VN KewalRamani. Suppression of viremia and evolution of HIV-1 drug resistance in a macaque model for antiretroviral therapy. J Virol 81:12145-12155 (2007).
Kimata, JT. HIV fitness and disease progression: Insights from the SIV-macaque model. Current HIV Research 4:65-77 (2006).
Patel PG, MT Yu Kimata, JE Biggins, J Wilson and JT Kimata. Highly pathogenic simian immunodeficiency virus variants that emerge during the course of infection evolve enhanced infectivity but do not efficiently down modulate class I major histocompatibility complex antigens. J Virol 76:6425-6434 (2002).
Kimata, JT, L Kuller, D Anderson, P Dailey, and J Overbaugh. Emerging cytopathic and antigenic SIV variants influence AIDS progression. Nature Med 5:535-541, (1999).
For more publications, see listing on PubMed.
Molecular Virology & Microbiology