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Howard Hughes Medical Institute and Department of Medicine
Molecular Biology & Genetics; Pharmacology and Molecular Sciences; Biology (KSAS)
733 N. Broadway
Baltimore MD 21205
Host-virus interaction in HIV infection
For the 34 million people infected with HIV-1, the best current hope for avoiding the fatal consequences of the infection lies in treatment with antiretroviral therapy (ART), which consists of combinations of three drugs that inhibit specific steps in the virus life cycle. The benefits of ART in reducing the morbidity and mortality are clear, but ART is not curative. In 1995, our laboratory provided the first demonstration that latently infected CD4+ T cells were present in patients with HIV-1 infection. We later found that latently infected cells persist indefinitely even in patient on prolonged ART. These studies indicated that eradication of HIV-1 infection with ART alone would never be possible. The latent reservoir for HIV-1 in resting CD4+ T cells is now widely recognized as the major barrier to curing HIV-1 infection and is the subject of an intense international research effort. Our laboratory has gone on to characterize the different forms of HIV-1 that persist in patients on ART and to explore potential strategies for eradicating the virus. In particular, we are searching for and evaluating drugs that target the latent reservoir. We are also developing assays that can be used to monitor the elimination of this reservoir in patients participating in eradication trials. The laboratory is also interested in the 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 are so effective at inhibiting viral replication. We are using this discovery along with experimental and computational approaches to develop improved therapies for HIV-1 infection and to understand and prevent drug resistance. Finally we are studying the immunology of HIV-1 infection, and in particular, the ability of some patients to control the infection without ART.
Ho, Y.C., Shan, L., Hosmanie, N.N., Wang, J., Laskey, S.B., Rosenbloom, D.I., Lai, J., Blankson, J.N., Siliciano, J.D., and Siliciano, R.F. (2013). Replication-competent non-induced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell
Rabi, S.A., Laird, G.M., Durand, C.M., Laskey, S., Shan, L., Bailey, J.R., Chioma, S., Moore, R.D., and Siliciano, R.F. (2013). Multi-step inhibition explains HIV-1 protease inhibitor pharmacodynamics and resistance. J. Clin. Invest.
Eriksson, S., Graf, E.H., Dahl, V., Strain, M.C., Yukl, S.A., Lysenko, E.S., Bosch, R.J., Lai, J., Chioma, S., Emad, F. Abdel-Mohsen M, Hoh R, Hecht F, Hunt P, Somsouk M, Wong J, Johnston R, Siliciano RF, Richman DD, O'Doherty U, Palmer S, Deeks SG, Siliciano JD., et al. (2013). Comparative Analysis of Measures of Viral Reservoirs in HIV-1 Eradication Studies. PLoS Pathog. 9, e1003174.
Goldberg, D.E., Siliciano, R.F., and Jacobs, W.R.,Jr. (2012). Outwitting Evolution: Fighting Drug-Resistant TB, Malaria, and HIV. Cell 148, 1271-1283.
Jilek, B.L., Zarr, M., Sampah, M.E., Rabi, S.A., Bullen, C.K., Lai, J., Shen, L., and Siliciano, R.F. (2012). A quantitative basis for antiretroviral therapy for HIV-1 infection. Nat. Med. 18, 446-451.
Laird, G.M., Eisele, E.E., Rabi, S.A., Lai, J., Chioma, S., Blankson, J.N., Siliciano, J.D., and Siliciano, R.F. (2013). Rapid quantification of the latent reservoir for HIV-1 using a viral outgrowth assay. PLoS Pathog. 9, e1003398.
Rosenbloom, D.I., Hill, A.L., Rabi, S.A., Siliciano, R.F., and Nowak, M.A. (2012). Antiretroviral dynamics determines HIV evolution and predicts therapy outcome. Nat. Med. 18, 1378-1385.
Shan, L., Deng, K., Shroff, N.S., Durand, C.M., Rabi, S.A., Yang, H.C., Zhang, H., Margolick, J.B., Blankson, J.N., and Siliciano, R.F. (2012). Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation. Immunity 36, 491-501.
Sampah, M.E., Shen, L., Jilek, B.L., and Siliciano, R.F. (2011). 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.
Shen, L., Rabi, S.A., Sedaghat, A.R., Shan, L., Lai, J., Xing, S., and Siliciano, R.F. (2011). A critical subset model provides a conceptual basis for the high antiviral activity of major HIV drugs. Sci. Transl. Med. 3, 91ra63.