T-Lymphocytes; RNA Interference; RNA, Small Interfering; Infectious Disease Medicine; Molecular Targeted Therapy
Molecular Virology: Virology laboratories
My laboratory is involved in developing novel RNA interference (RNAi)-based strategies for treating viral infections. RNAi is a gene silencing mechanism in which 19-21 nucleotide double-stranded RNAs called small interfering RNAs (siRNAs) can guide the destruction of complementary cellular mRNAs with a high degree of specificity. A major challenge in using RNAi-based therapies in vivo is the targeted delivery of siRNAs to specific tissues/cells of interest. Targeted delivery would not only improve efficacy but also reduce potential side effects of RNAi therapy.
Towards this goal we have recently developed a novel method for the specific delivery of siRNAs into human T cells and tested in vivo efficacy using “humanized mice”: (immunodeficient mice transplanted with human hematopoietic stem cells and consequently a human immune system). Antiviral siRNAs delivered by this approach could control HIV in these mice demonstrating the feasibility of RNAi therapy for HIV infection.
Specialized Terms: RNA interference (RNAi)-based strategies for treating viral infections
Extensive Research Description
The current focus of my lab is to refine the above methods and use them to investigate key aspects of HIV immunopathogenesis and AIDS-associated T cell loss. In addition we have also developed a novel method for the specific delivery of siRNAs into neuronal cells and used this to treat flaviviral encephalitis in mouse models. My lab is presently using this approach to investigate the pathogenesis of flaviviral infections. The long term goals are to translate this research into viable HIV-AIDS and anti-flaviviral therapy.
- RNAi-mediated CCR5 silencing by LFA-1-targeted nanoparticles prevents HIV infection in BLT mice. Kim SS, Peer D, Kumar P**, Subramanya S, Wu H, Asthana D, Habiro K, Yang YG, Manjunath N, Shimaoka M, Shankar P. Mol Ther. 2010 Feb;18(2):370-6. doi: 10.1038/mt.2009.271. Epub 2009 Dec 8.
- Kumar P, Ban HS, Kim SS, Wu H, Pearson T, Greiner D, Laouar A, Yao J, Haridas V, Habiro K, Yang YG, Jeong JH, Lee KY, Kim YK, Kim SW, Peipp M, Fey GH, Manjunath N, Shultz LN, Lee SK and Shankar P. (2008). T cell-specific siRNA delivery suppresses HIV-1 infection in humanized mice. Cell. 134(4):577-86.
- Effective suppression of HIV-1 by artificial bispecific miRNA targeting conserved sequences with tolerance for wobble base-pairing. Son J, Kim YB, Shankar P, Kumar P* and Lee SK. Biochem Biophys Res Commun. 2008 Sep 19;374(2):214-8. doi: 10.1016/j.bbrc.2008.06.125. Epub 2008 Jul 11.
- Kumar P, Wu H, McBride JL, Jung KE, Moon Hee Kim, Davidson BL, Lee SK, Shankar P and Manjunath N. (2007). Transvascular delivery of small interfering RNA to the central nervous system. Nature. 448(7149):39-43.
- Kumar P, Lee SK, Shankar P and Manjunath N. A single siRNA suppresses fatal encephalitis induced by two different flaviviruses. PLOS Medicine 2006 3(4):e96
- Kumar P, Lee SK, Shankar P and Manjunath N. A single siRNA suppresses fatal encephalitis induced by two different flaviviruses. PLOS Medicine 2006 Feb 14;3(4):e96. PMCID: PMC1361782