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Case Western Reserve University

MOLECULAR BIOLOGY
and MICROBIOLOGY

 
 
       
 

 

Jonathan Karn


Reinberger Professor of Molecular Biology
Chairman
Director, Case Center for AIDS Research

Control of Gene Expression and Latency in HIV, and Strategies for Viral Eradication

Office Phone: 216-368-3915
Office Fax: 216.368.3055
email: jonathan.karn@case.edu


     
 

HIV persists in the face of highly active antiretroviral therapy (HAART) due to constitutive low-level replication in sites that are poorly accessible to drugs and the development of latent infections in a variety of types including the long-lived memory CD4+ T cell population, macrophages, and microglial cells in the brain - cells that play a critical role in neurologic dysfunction and neurotoxicity.  Although HAART has greatly extended survival to patients infected with HIV-1, current therapy has failed to decrease the prevalence of HIV-neurological diseases especially in individuals who abuse drugs. Our research focuses on defining the molecular basis for HIV silencing, the signaling pathways used to reactivate latent HIV, the impact of drugs of abuse on the creation and reactivation of the latent viral reservoir in microglial cells, and the development of novel therapeutic approaches to attacking HIV latency. Key questions about HIV silencing that remain to be answered include: What are the primary sequence triggers and mechanisms that induce silencing (i.e. protein repressors and/or viral-derived RNA)? What cellular pre-conditions lead to proviral silencing?  Do similar silencing mechanisms operate in each of the cell types infected by HIV?  How do drugs of abuse reactivate HIV?  In partial answer to these questions we have demonstrated that distinct epigenetic silencing mechanisms lead to viral persistence in different cell types.  Using novel unbiased shRNA screens we have shown that in T-cells, the polycomb repressive complex 2 (PCR2) plays a central role in maintaining proviral latency, whereas in microglial cells, PCR2 is absent and silencing is mediated by the SMRT and CoREST silencing machinery.  Because of these differences in the silencing machinery we have been able to identify selective activators of HIV transcription in the two different cell types.  Extending this work we plan to develop novel technologies allowing exploitation a natural epigenetic silencing mechanisms involving both histone and DNA methylation, to block HIV transcription.  Our laboratory has developed an extensive network of collaborations with academic and pharmaceutical partners as part of our work on HIV eradication.  Our laboratory is a participant in the Martin Delaney Collaboratory of AIDS Researchers for Eradication (CARE), a network of twenty leading laboratories working on HIV eradication strategies, the amfAR Research Consortium on HIV Eradication (ARCHE), the HIV Reservoirs and Viral Eradication Transformative Science Group (TSG) of the AIDS Clinical Trials Group (ACTG) and we are also working in close collaboration with Merck on identification of novel HIV therapeutics.

Selected Publications

Wires ES, Alvarez D, Dobrowolski C, Wang Y, Morales M, Karn J, Harvey BK (2012) Methamphetamine activates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and induces human immunodeficiency virus (HIV) transcription in human microglial cells. J Neurovirol. [Epub ahead of print] [PubMed]

Mbonye U, Karn J (2012) Control of HIV latency by epigenetic and non-epigenetic mechanisms. Curr HIV Res. 9(8):554-67. [PubMed]

Kim YK, Mbonye U, Hokello J, Karn J (2011) T-cell receptor signaling enhances transcriptional elongation from latent HIV proviruses by activating P-TEFb through an ERK-dependent pathway. J Mol Biol. 2011 Jul 29;410(5):896-916. [PubMed]

Friedman J, Cho WK, Chu CK, Keedy KS, Archin NM, Margolis DM, Karn J (2011) Epigenetic silencing of HIV-1 by the histone H3 lysine 27 methyltransferase enhancer of Zeste 2. J. Virol. 85(17):9078-89. [PubMed]

Lalonde MS, Lobritz MA, Ratcliff A, Chamanian M, Athanassiou Z, Tyagi M, Wong J, Robinson JA, Karn J, Varani G, Arts EJ (2011) Inhibition of both HIV-1 reverse transcription and gene expression by a cyclic peptide that binds the Tat-transactivating response element (TAR) RNA. PLoS Pathog. 7(5):e1002038. [PubMed]

Karn J (2011) The molecular biology of HIV latency: breaking and restoring the Tat-dependent transcriptional circuit. Curr Opin HIV AIDS. 6(1):4-11. [PubMed]

Tyagi M, Pearson RJ, Karn J (2010) Establishment of HIV latency in primary CD4+ cells is due to epigenetic transcriptional silencing and P-TEFb restriction. J Virol. 84(13):6425-37. [PubMed]

Davidson A, Leeper TC, Athanassiou Z, Patora-Komisarska K, Karn J, Robinson JA, Varani G (2009) Simultaneous recognition of HIV-1 TAR RNA bulge and loop sequences by cyclic peptide mimics of Tat protein. Proc Natl Acad Sci U S A. 106(29):11931-6. [PubMed]

Pearson R, Kim YK, Hokello J, Lassen K, Friedman J, Tyagi M, Karn J (2008) Epigenetic silencing of human immunodeficiency virus (HIV) transcription by formation of restrictive chromatin structures at the viral long terminal repeat drives the progressive entry of HIV into latency. J Virol. 82(24):12291-303. [PubMed]

Tyagi M, Karn J (2007) CBF-1 promotes transcriptional silencing during the establishment of HIV-1 latency. EMBO J. 26(24):4985-95.[PubMed]

Kim YK, Bourgeois CF, Pearson R, Tyagi M, West MJ, Wong J, Wu SY, Chiang CM, Karn J: Recruitment of TFIIH to the HIV LTR is a rate-limiting step in the emergence of HIV from latency. EMBO J. 2006 Aug 9;25(15):3596-604. [PubMed]

 

Complete list of Publications