Matt (Edward) Kennedy
- 2010 - Outstanding Graduate Student Poster Award Developmental Center for AIDS Research - World AIDS Day Symposium
Matt Kennedy entered the Microbiology PhD program in July of 2006, following service in the U.S. Peace Corps. Subsequent to a number of laboratory rotations, he joined the laboratory of Dr. Baek Kim in January 2007. He subsequently earned his Master of Science degree in the Fall of 2008 and is currently in the final phase of his PhD.
Drug resistance and evasion of the host immune defense by pathogens arise durning chronic infection as a result of selection among diverse genetic variants generated during replication of the pathogen. Some retroviruses and RNA viruses have the potential for massive quasispecies diversity within a single host—which manifests rapidly after transmission—and makes these pathogens exceedingly difficult to treat with drugs and vaccines. Examples include rapid emergence of multi drug resistant HIV-1 strains and the constant, genetic drift of the influenza virus. Matt’s research focues on the generation of viral mutations and how this drives viral evasion of the host defense and emergence of drug resistance. His work investigates the role of the HIV-1 RNA/DNA dependent DNA polymerase, reverse transcriptase (RT), in these processes. RT is a low fidelity polymerase that makes errors during DNA synthesis at least 100 fold more frequently than the polymerases that replicate cellular genomes. The RT driven mutation rate also differs depending on the cell type that HIV-1 infects, typically CD4+ T cells and macrophage. These cells greatly differ in that CD4+ T cells are activated during infection and dividing, which facilitates essential proviral DNA synthesis. In contrast macrophages are non-dividing and terminally differentiated cells. Non-dividing macrophages will never replicate their cellular DNA again; and have exceedingly low levels of the substrate for DNA synthesis, 2´ deoxyribose triphosphates (dNTPs). There are well established links between low, imbalanced dNTP pools and mutation synthesis, and this is one major focus of the work in our lab. Specifically my work focuses on both the impact and mechanism of incorporation of non-canonical DNA nucleotides rNTPs and dUTP by RT in macrophages where dNTPs are scarce.
- Kennedy, E. M., W. Daddacha, R. Slater, C. Gavegnano, E. Fromentin, R. F. Schinazi, and B. Kim. Abundant non-canonical dUTP found in primary human macrophages drives its frequent incorporation by human immunodeficiency virus type 1 reverse transcriptase. J Biol Chem. In Press March 2011
Kennedy, E. M., C. Gavegnano, L. Nguyen, R. Slater, A. Lucas, E. Fromentin, R. F. Schinazi, and B. Kim. Ribonucleoside triphosphates as substrate of human immunodeficiency virus type 1 reverse transcriptase in human macrophages. J Biol Chem 285:39380-91.
Kennedy, E. M., C. Gavegnano, L. Nguyen, R. Slater, A. Lucas, E. Fromentin, R. F. Schinazi, and B. Kim. HIV-1 RT Mediated Mutation Synthesis During DNA Polymerization in Macrophages Nucleotide Pools.
Poster Presentation Cold Spring Harbor Retroviruses 2010
Kennedy, E. M., C. Hergott, S. Dewhurst, and B. Kim. 2009. The mechanistic architecture of thermostable Pyrococcus furiosus family B DNA polymerase motif A and its interaction with the dNTP substrate. Biochemistry 48:11161-8.
Isabella, V. M., J. D. Lapek, Jr., E. M. Kennedy, and V. L. Clark. 2009. Functional analysis of NsrR, a nitric oxide-sensing Rrf2 repressor in Neisseria gonorrhoeae. Mol Microbiol 71:227-39.
Kennedy, E. M. Baek Kim HIV-1 RT mismatch extension dissected: Q151 directly facilitates conformational change (Kpol) required for mutation synthesis. Poster Presentation Cold Spring Harbor Retroviruses 2007