[ Publications ] [ Contact Info ]

Research Interests

Studies in my laboratory focus on 5 main areas of HIV research: i) Characterization of factors that determine viral entry into target cells; ii) Analysis of molecular mechanisms of HIV-1 translocation from the cytoplasm into the nucleus of infected cell; iii) Studies of the activity of Vpr, an HIV protein important for disease pathogenesis; iv) Design and analysis of anti-HIV compounds that target nuclear translocation; v) Studies of HIV infection in macrophages; vi) Analysis of cholesterol metabolism in HIV-infected cells

Along these lines, we have made the following major discoveries:

1. In the course of our studies of the early steps of HIV-1 infection of target cells, we have identified a novel factor involved in HIV-1 entry. This molecule, CD147, serves as a receptor for virus -incorporated cyclophilin A and also for extracellular cyclophilins A and B. Our current work is aimed at the molecular mechanisms of cyclophilin-CD147 interaction during HIV-1 infection. We are also investigating the involvement of this interaction in regulation of immune responses and in the pathogenesis of other diseases associated with high levels of cyclophilin, such as rheumatoid arthritis. These studies are expected to suggest novel therapeutic approaches for treating these diseases.

2. Our laboratory pioneered studies of HIV-1 nuclear transport mechanisms and we were the first to describe the role of matrix protein and Vpr in this process. We continue these studies focusing on interactions between Vpr and cellular proteins. In addition to contributing to our understanding of HIV-1 biology, results of these studies are expected to provide a basis for design of compounds targeting Vpr.

3. We have designed a series of compounds that target HIV-1 nuclear import. These compounds are now in pre-clinical development stage by ITI, Inc., a Seattle-based start-up company. We also investigated the anti-HIV activity of the B-oligomer of pertussis toxin and demonstrated a plethora of unusual anti-HIV activities of this molecule.

4. We have found that HIV-1 infection of macrophages induces secretion of *-chemokines and have analyzed the molecular mechanisms involved in *-chemokine production. Our group published a seminal paper in Nature demonstrating that *-chemokines do not inhibit HIV-1 infection of these cells (Schmidtmayerova et al., 1996). A series of reports from our laboratory has demonstrated the production of nitric oxide by HIV-infected macrophages and the role of this mechanism in neuropathology of HIV infection. We also analyzed the effect of activation on HIV infection of macrophage and T cells and demonstrated that activating stimuli, such as LPS, protect macrophages from infection.

Selected Publications [ top ]

Pushkarsky T, Yurchenko V, Vanpouille C, Brichacek B, Vaisman I, Hatakeyama S, Nakayama KI, Sherry B, and Bukrinsky M (2005). Cell surface expression of CD147/emmprin is regulated by cyclophilin 60. J. Biol. Chem. 280:27866-27871.

Arora K, Gwinn WM, Bower MA, Watson A, Okwumabua I, Macdonald HR, Bukrinsky M, and Constant SL. (2005). Extracellular cyclophilins contribute to the regulation of inflammatory responses. J. Immunol. 175:517-522.

Haffar O, Dubrovsky L, Lowe R, Berro R, Kashanchi F, Godden J, Vanpouille C, Bajorath J, and Bukrinsky M (2005). Oxadiazols: a new class of rationally designed anti-HIV compounds targeting nuclear localization signal of the viral matrix protein. J. Virol. 79:13028-13036.

Yurchenko V, Pushkarsky T, Li JH, Dai WW, Sherry B, and Bukrinsky M (2005). Regulation of CD147 cell surface expression: involvement of the proline residue in the CD147 transmembrane domain. J. Biol. Chem. 280:17013-17019.

Iordanskiy S., Zhao Y., Dubrovsky S., Iordanskaya T., Chen M., Liang D., and Bukrinsky M (2004). Heat-shock protein 70 protects cells from cell cycle arrest and apoptosis induced by HIV-1 viral protein R. J. Virol. 78:9697-9704.

Bukrinsky M and Zhao Y (2004). Heat-shock proteins reverse the G2 arrest caused by HIV-1 viral protein R. DNA Cell Biol. 23:223-225.

Iordanskiy S., Zhao Y., DiMarzio P., Agostini I., Dubrovsky L., and Bukrinsky M (2004). Heat-shock protein 70 exerts opposing effects on Vpr-dependent and Vpr-independent HIV-1 replication in macrophages. Blood, 104:1867-1872.

Bukrinsky M (2004). A hard way to the nucleus. Mol. Med. 10:1-6.

Benko Z, Hou J, Liang D., Chiu K., Taricani L., Yu M., Innis S., Reed P., Kabat W., Agbottah E., Di Marzio P., Young P.G., Bukrinsky M, and Zhao Y. (2004). Antagonistic interactions between small heat shock proteins and HIV-1 viral protein R. J. Virol. 78:11016-11029.

Haffar O and Bukrinsky M (2005). Nuclear translocation as a novel target for anti-HIV drugs. Expert Rev. Anti Infect. Ther. 3:41-50.

DiMarzio PD, Sherry B, Thomas EK, Franchin G, Schmidtmayerova H, Bukrinsky M. Beta-chemokine production in CD40L-stimulated monocyte-derived macrophages requires activation of MAPK signaling pathways. Cytokine. 2003 Aug 7;23(3):53-63.

Iordanskiy S, Iordanskaya T, Quivy V, Van Lint C, Bukrinsky M. B-oligomer of pertussis toxin inhibits HIV-1 LTR-driven transcription through suppression of NF-kappaB p65 subunit activity. Virology. 2002 Oct 10;302(1):195-206.

Brichacek B, Bukrinsky M. Highly active antiretroviral therapy and beta-chemokines. Clin Exp Immunol. 2002 Nov;130(2):169-71.

Twu C, Liu NQ, Popik W, Bukrinsky M, Sayre J, Roberts J, Rania S, Bramhandam V, Roos KP, MacLellan WR, Fiala M. Cardiomyocytes undergo apoptosis in human immunodeficiency virus cardiomyopathy through mitochondrion- and death receptor-controlled pathways. Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14386-91.

Al-Abed Y, Dubrovsky L, Ruzsicska B, Seepersaud M, Bukrinsky M. Inhibition of HIV-1 nuclear import via schiff base formation with arylene bis(methylketone) compounds. Bioorg Med Chem Lett. 2002 Nov 4;12(21):3117

Bukrinsky MI. Cyclophilins: unexpected messengers in intercellular communications. Trends Immunol. 2002 Jul;23(7):323-5.

Liu NQ, Lossinsky AS, Popik W, Li X, Gujuluva C, Kriederman B, Roberts J, Pushkarsky T, Bukrinsky M, Witte M, Weinand M, Fiala M. Human immunodeficiency virus type 1 enters brain microvascular endothelia by macropinocytosis dependent on lipid rafts and the mitogen-activated protein kinase signaling pathway.J Virol. 2002 Jul;76(13):6689-700.

Yurchenko V, Zybarth G, O'Connor M, Dai WW, Franchin G, Hao T, Guo H, Hung HC, Toole B, Gallay P, Sherry B, Bukrinsky M. Active site residues of cyclophilin A are crucial for its signaling activity via CD147. J Biol Chem. 2002 Jun 21;277(25):22959-65.

Agostini I, Popov S, Hao T, Li JH, Dubrovsky L, Chaika O, Chaika N, Lewis R, Bukrinsky M. Phosphorylation of Vpr regulates HIV type 1 nuclear import and macrophage infection. AIDS Res Hum Retroviruses. 2002 Mar 1;18(4):283-8.

Fiala M, Gujuluva C, Berger O, Bukrinsky M, Kim KS, Graves MC. Chemokine receptors on brain endothelia--keys to HIV-1 neuroinvasion? Adv Exp Med Biol. 2001;493:35-40.

Contact Information [ top ]

Michael Bukrinsky M.D., Ph.D.
Professor and Vice Chairman
Department of Microbiology and Tropical Medicine
The George Washington University
Ross Hall, Rm 734
2300 Eye St. NW
Washington DC 20037
phone:202-994-2036
fax:202 994 2913
email:mtmmib@gwumc.edu