Research

INDIVIDUAL RESEARCHER

Mario Canki , Ph.D
Assistant Professor
e-mail: cankim@mail.amc.edu

Education

1995 - Ph.D from New Jersey Medical School, Newark, NJ

Current Research

This laboratory investigates mechanisms of HIV pathogenesis with an eye on potential clinical applications. We are interested in the course of HIV-1 infection in the Central Nervous System (CNS), focusing on infection of astrocytes and its effects on cell function contributing to the pathogenesis of AIDS dementia complex (ADC). Astrocytes are a target for HIV-1 in the brain, and reports have shown that from 0.8% to as many as 20% of astrocytes are infected by HIV-1 in vivo. Considering that the number of astrocytes in the brain ranges between 4 x 10¹¹ and 2 x 10¹² cells, the total number of HIV-1 infected astrocytes in vivo may be substantial. This reservoir of latent and inducible HIV-1 in astrocytes may be responsible for the continuous dissemination of HIV-1 in the CNS that must be considered if total virus eradication is to be achieved. We developed a model system of efficient HIV-1 infection of primary astrocytes that allows for studies on the course of the HIV-1 life cycle in these cells. The initial efficient virus expression declines over time to a low productive, chronic infection from which virus can be induced by physiological stimuli. This newly developed system represents a valuable model of viral latency. It permits detailed studies on the molecular mechanisms of HIV infection in these cells by conventional quantitative biochemical techniques, previously not possible. It is our hypothesis that the efficient early HIV-1 expression in astrocytes induces cellular restrictions to further viral replication and alters the infected cell physiology. It is our interest to investigate and determine specific routes to neuropathogenesis including excess unintegrated viral DNA, expression of regulatory versus structural RNA and protein, and establishment of reservoirs for continued production of infectious HIV-1 in the brain. Regulation of viral transcription, and cellular factors acting on the HIV-1 LTR contributing and modulating viral restriction is of particular interest especially in the context of latency. Because of the centrality of transcriptional factors in controlling gene expression these experiments are likely to be pivotal. Just as elucidation of transcriptional control in T cells has been crucial in understanding control of viral expression in these cells, clarification of transcriptional control in astrocytes has the same ramification. We are also investigating activation of select cellular genes and their function relevant to virus infection and replication. Production and secretion of cytokines and chemokines from infected astrocytes is being examined to better understand pathways contributing to cell activation, recruitment of microglia, macrophages, and T cells to the site of infection. Overall, laboratory research interests are to elucidate mechanisms regulating viral life cycle in astrocytes, utilizing astrocyte infection as a model system for gaining greater understanding of cell-virus interactions. Experiments with novel antiviral compounds are producing promising results and are currently under investigation.

Postdoctoral Position Available

A postdoctoral position is available to study in this laboratory. Contact Dr. Canki for additional details.

References

1. Jinliang Li, Volsky, D.J., Ghorpade, A. and Canki, M. HIV-1 induces MCP-1 and RANTES production in human fetal astrocytes: requirement for virus replication and independence of NF-kB induction pathway. (In preparation.)



2. Canki, M., Thai, J. N. F., Chao, W., Ghoparde, A., Potash, M. J., and Volsky, D. J. Highly productive infection with pseudotyped human immunodeficiency virus type 1 (HIV-1) indicates no intracellular restrictions to HIV-1 replication in primary human astrocytes. J. Virol. 75, 17:7925-7933, 2001.



3. Canki, M., Sparrow, J., Chao, W., Potash, M. J., and Volsky, D. J. Human immunodeficiency virus type 1 can infect human retinal pigment epithelial cells in culture and alter the ability of the cells to phagocytose rod outer segment membranes. AIDS Res. Hum. Retroviruses. 16:453-463, 2000.



4. Bencheikh, M., Bentsman, G., Sarkissian, N., Canki, M., and Volsky, D. J. Replication of different clones of human immunodeficiency virus type 1 in primary fetal human astrocytes: enhancement of viral gene expression by Nef. J. NeuroVirol. 5:115-124, 1999.



5. Canki, M., Potash, M. J., Bentsman, G., Chao, W., Flynn, T., Heinemann, M., Gelbard, H., and Volsky, D. J. Isolation and long-term culture of primary ocular human immunodeficiency virus type 1 isolates in primary astrocytes. J. NeuroVirol. 3:19-15, 1997.