Department Affiliation: Medicine; Molecular Biology and Genetics, Howard Hughes Medical Institute
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, Broadway 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:
- Bailey, J.R., Williams, T.M., Siliciano, R.F., Blankson,J.N . Maintenance of viral suppression inHIV-1-infected HLA-B*57+ elite suppressors despite CTL escape mutations. J. Exp. Med. 203:1357-1369, 2006. Pub Med Reference
- Bailey, J.R., Sedaghat, A.R., Kieffer, T., Brennan, T., Lee, P,K., Wind-Rotolo, M., Haggerty, C.M., Kamireddi, A.R., Liu, Y., Lee, J., Persaud, D., Gallant, J.E., Cofrancesco, Jr., J., Quinn,T.C. , Wilke, C.O., Ray, S.C., Siliciano, J.D., Nettles, R.E., Siliciano, R.F.. Residual human immunodeficiency virus type 1 viremia in some patients on antiretroviral therapy is dominated by a small number of invariant clones rarely found in circulating CD4+T cells. J. Virol. 80:6441-6457, 2006. Pub Med Reference
- Lassen KG, KX Ramyar, JR Bailey, Y Zhou, RF Siliciano. Nuclear retention of multiply spliced HIV-1 RNA in resting CD4+ T cells. PloS Pathogens 2:68 (2006). Pub Med Reference
- Blankson JN, JR Bailey, S Thayil, HC Yang, K Lassen, J Lai,SK Gandhi, JD Siliciano, TM Williams, RF Siliciano. Isolation and characterization of replication-competent HIV-1 from a subset of elite suppressors. J Virol. 81:2508-2518, 2006. 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., Chong, C.R., Liu, J.O., Siliciano, R.F., Thio, T.L.. The HBV drug entecavir – effects on HIV-1replication and resistance. New Engl J Med 356:2614-2621, 2007. Pub Med Reference
- Sedaghat, A.R., Siliciano, J.D., Brennan, T.P., Wilke, C.O., Siliciano, R.F. Limitson replenishment of the resting CD4+ T cell reservoir for HIV in patients on HAART. PloS Pathogens 3:1165-1174, 2007. Pub Med Reference
- Gandhi, S.K., Siliciano, J.D. , Bailey, J.R., Siliciano, R.F., Blankson, J.N. The role of APOBEC3G/F-mediated hypermutation in the control of HIV-1 in elite suppressors. J. Virol. 82:3125-3130, 2007. Pub Med Reference
- Sedaghat, A.R., German, J., Teslovich, T.M. , Cofranceso, Jr., J., Jie, C.C., Talbot, Jr., C.C., Siliciano, R.F.. Chronic CD4+ T cell activation and depletion in HIV-1 Infection: Type I interferon-mediated disruption of T cell dynamics. J. Virol. 82:1870-1883, 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
- 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. , 2009 [Epub ahead of print]. Pub Med Reference
- Sedaghat A.R., Siliciano, R.F., Wilke, C.O. Constraints on the dominant mechanism for HIV viral dynamics in patients on raltegravir. Antivir. Ther. 14(2):263-271, 2009. Pub Med Reference
- Lassen, K.G., Lobritz, M.A., Bailey, J.R., Johnston, S., Nguyen, S., Lee, B., Chou, T., Siliciano, R.F., Markowitz, M., Arts, E.J. Elite suppressor-derived HIV-1 envelope glycoproteins exhibit reduced entry efficiency and kinetics. PLoS Pathog. (4):e1000377, 2009. Pub Med Reference
- Wind-Rotolo, M., Durand, C., Cranmer, L., Reid, A., Martinson, N., Doherty, M., Jilek, B.L., Kagaayi, J., Kizza, A., Pillay, V., Laeyendecker, O., Reynolds, S.J., Eshleman, S.H., Lau, B., Ray, S.C., Siliciano, J.D., Quinn, T.C., Siliciano, R.F. Identification of nevirapine-resistant HIV-1 in the latent reservoir after single-dose nevirapine to prevent mother-to-child transmission of HIV-1. J. Infect. Dis. 199(9):1301-1309, 2009. Pub Med Reference
- O'Connell, K.A., Han, Y., Williams, T.M., Siliciano, R.F., Blankson, J.N. Role of natural killer cells in a cohort of elite suppressors: low frequency of the protective KIR3DS1 allele and limited inhibition of human immunodeficiency virus type 1 replication in vitro. J. Virol. 83(10):5028-5034, 2009. Pub Med Reference
- Bailey, J.R., Brennan, T.P., O'Connell, K.A., Siliciano, R.F., Blankson, J.N. Evidence of CD8+ T-cell-mediated selective pressure on human immunodeficiency virus type 1 nef in HLA-B*57+ elite suppressors. J. Virol. 83(1):88-97, 2009. Pub Med Reference
Other graduate programs in which Dr. Siliciano participates:
