Robert F. Siliciano

Department Affiliation:  Primary:  Medicine; Molecular Biology and Genetics, Howard Hughes Medical Institute; Secondary:  Pharmacology and Molecular Sciences
Degree: M.D., Ph.D., Johns Hopkins University
Rank: Professor
Telephone Number: 410-955-2958
Fax Number: 443-287-6218
E-mail address: rsiliciano@jhmi.edu
School of Medicine Address: Room 879, Edward D. Miller Research Building, 733 N. Broadway, Baltimore, MD 21205 

Drug therapy for HIV infection.

For the staggering number of people infected with HIV-1 (33 million), the best current hope for avoiding the fatal consequences of the infection lies in treatment with highly active antiretroviral therapy (HAART), which consists of combinations of 3 drugs that inhibit specific steps in the virus life cycle.  The benefits of HAART in reducing the morbidity and mortality are clearly documented, but major questions remain about how best to use this therapy and how to make it available to all who need it.  Our lab has shown that in the vast majority of patients, current HAART regimens cannot cure the infection as a result of the existence of a very stable reservoir of latent virus in resting memory CD4+ T cells.  Because HAART is not curative, the treatment of HIV-1 infection is a lifelong challenge.  Unfortunately, problems of drug toxicity and the rapid development of drug resistance make this a formidable problem.  Our current research efforts are directed at understanding the basic molecular mechanisms of HIV-1 latency and drug resistance.  We are searching for drugs that can target the latent form of HIV.  In addition, we are focusing on basic pharmacodynamic principles that explain how antiretroviral drugs work.  We have recently uncovered a previously unrecognized form of intermolecular cooperatively that explains why certain classes of antiretroviral drugs can completely inhibit viral replication and are trying to use this discovery to develop improved therapies for HIV infection.

Representative Publications:

• Shen, L., Rabi, S.A., Sedaghat, A.R., Shan, L., Lai, J., Xing, S., Siliciano, R.F.  A critical subset model provides a conceptual basis for the high antiviral activity of major HIV drugs. Sci. Transl. Med.  Pub Med Reference

• Sampah, M.E., Shen, L., Jilek, B.L., Siliciano, R.F.  Dose-response curve slope is a missing dimension in the analysis of HIV-1 drug resistance. Proc. Natl. Acad. Sci. U.S.A. 108:7613-7618, 2011.  Pub Med Reference

• Shan, L., Yang, H.C., Rabi, S.A., Bravo, H.C., Shroff, N.S., Irizarry, R.A., Zhang, H., Margolick, J.B., Siliciano, J.D., Siliciano, R.F.  Influence of host gene transcription level and orientation on HIV-1 latency in a primary-cell model. J. Virol. 85:5384-5393, 2011.  Pub Med Reference

• Xing, S., Bullen, C.K., Shroff, N.S., Shan, L., Yang, H.C., Manucci, J.L., Bhat, S., Zhang, H., Margolick, J.B., Quinn, T.C., et al.  Disulfiram reactivates latent HIV-1 in a Bcl-2-transduced primary CD4+ T cell model without inducing global T cell activation.  J. Virol. 85:6060-6064, 2011.  Pub Med Reference

• Dinoso, J.B., Kim, S.Y., Wiegand, A.M., Palmer, S.E., Gange, S.J., Cranmer, L., O'Shea, A., Callender, M., Spivak, A., Brennan, T., et al.  Treatment intensification does not reduce residuatl HIV-1viremia in patients on highly active antiretroviral therapy.  Proc. Natl. Acad. Sci. U.S.A. 106:9403-9408, 2009.  Pub Med Reference

• Yang, H.C., Xing, S., Shan, L., O'Connell, K., Dinoso, J., Shen, A., Zhou, Y., Shrum, C.K., Han, Y., Liu, J.O., Zhang, H,. Margolick, J.B., Siliciano, R.F. Small-molecule screening using a human primary cell model of HIV latency identifies compounds that reverse latency without cellular activation. J. Clin. Invest. 119:3473-3486, 2009.  Pub Med Reference

• Han, Y., Lin, Y.B., An, W., Xu, J., Yang, H.C., O'Connell, K., Dordai, D., Boeke, J.D., Siliciano, J.D.,  Siliciano, R.F.  Orientation-dependent regulation of integrated HIV-1 expression by host gene transcriptional readthrough.  Cell. Host Microbe 4:134-146, 2008.  Pub Med Reference

• Sedaghat, A.R., Dinoso, J.B., Shen, L.,  Wilke, C.O., Siliciano, R.F.  Decay dynamics of HIV-1 depend on the inhibited stages of the viral life cycle.  Proc. Natl. Acad. Sci. USA 105:4832-4837, 2008.  Pub Med Reference

• Shen, L., Peterson. S., Sedaghat, A.R., McMahon, M.A., Callender, M., Zhang, H., Zhou, Y., Pitt, E.,  Anderson, K.S., Acosta, E.P.,  Siliciano, R.F.. Dose-response curve slope sets class-specific limits on inhibitorypotential of anti-HIV drugs.  Nature Med. 14(7):762-766, 2008.  Pub Med Reference

• McMahon, M.A., Jilek, B.L., Brennan, T.P., Shen, L., Zhou, Y., Wind-Rotolo, M., Xing, S., Bhat, S., Hale, B., Hegarty, R., et al.  The HBV drug entecavir - effects on HIV-1 replication and resistance. N. Engl. J. Med.  356:2614-2621, 2007.  Pub Med Reference

Other graduate programs in which Dr. Siliciano participates:

Biochemistry, Cellular and Molecular Biology
Cellular and Molecular Medicine
Immunology