Dr. Karn’s group is known for its studies of the mechanism of action of the HIV regulatory proteins, Tat and Rev, and the regulation of HIV transcription and latency.
In the late 1980s and early 1990s, while he was working at the MRC Laboratory of Molecular Biology in Cambridge England, Dr. Karn and his team discovered that the HIV regulatory proteins, Tat and Rev, are RNA binding proteins, and performed detailed studies of their interactions with their cognate RNAs. Subsequent work exploited cell-free transcription systems to demonstrate that Tat control of HIV transcription elongation is mediated by phosphorylation of key cofactors, including the RNA polymerase CTD itself and the Spt5 protein. Since arriving at Case in mid-2002, Dr. Karn’s group has continued detailed molecular studies of HIV transcription, with an emphasis on how HIV enters and exits from latency. The group was one of the first to demonstrate that HIV transcription is regulated by epigenetic silencing, and recently showed that silencing is mediated by the polycomb repressor complex 2. These studies involve extensive use of shRNA introduced by lentiviral vectors, and high-resolution chromatin immunoprecipation experiments (ChIP and ChIP-Seq) to study transcriptional and chromatin changes. In 2010, Dr. Karn received a NIDA Avant Garde award to exploit epigenetic silencing mechanisms to limit HIV reactivation from latency. As part of this work, the group has been studying HIV infection of microglial cells. In this system, HIV readily becomes latent and is rapidly and potently reactivated by drugs of abuse, including cocaine and methamphetamine. The impact of proviral reactivation by drugs of abuse on the development of NeuroAIDS is currently being studied in collaboration with Dr. Brandon Harvey at NIDA. In other recent work, the group has used advanced proteomics to discover a new activation pathway for P-TEFb, the essential cofactor of Tat, which involves the ERK-dependent phosphorylation of specific residues of the CDK-9 subunit. The group is also a participant in the NIH-funded Martin Delaney Collaboratory, a network of 20 leading HIV investigators and Merck, which is investigating new pharmacological approaches to eradicate HIV. As part of this program, Dr. Karn’s group has been defining the mechanism of action of compounds that activate latent HIV using primary cell and transformed cell models for HIV latency. Dr. Karn is also a consultant for the AIDS Clinical Trial Study Group on HIV eradication and a member of the amFAR ARCHES consortium on HIV eradication. Dr. Karn has published more than 100 papers and is an inventor on eight issued patent families. He has been the Executive Editor of the Journal of Molecular Biology since 1989. From 1987 to 1998, he played a leading role in the establishment and coordination of the UK’s research effort into AIDS as a member of the MRC AIDS Directed Program Steering Committee, and subsequently, the MRC’s Physiological Medicine and Infectious Diseases Board. He was Chairman of the NIH AIDS Cell and Molecular Biology Study Section from 2005 to 2007 and was recently appointed for a four-year term on the NIAID Advisory Council.