| Baek
Kim
Associate Professor of Microbiology & Immunology Primary Appointment: GEBS
Cluster Affiliations: | |
| Contact Information | ||
| University
of Rochester School of Medicine and Dentistry 601 Elmwood Ave, Box 672 Rochester, New York 14642 | Medical
Center 3-9611 Phone: (585) 275-6916 Fax: (585) 473-9573 E-Mail: baek_kim@urmc.rochester.edu |
|
- Research Focus
- HIV-1 replication, evolution, macrophage infectivity and brain reservoirs: Structure and function of Avian Influenza Virus RNA polymerase
- Research Overview
- My research interests focus on the following areas:
- Replicational fidelity of HIV reverse transcriptase: A bacterial genetic selection system coupled with random mutagenesis is being used to obtain active HIV RT mutants with altered fidelity (fidelity mutants). We are currently targeting the dNTP binding site and the catalytic site of HIV RT. We are focusing on understanding the mechanism of mutation synthesis by HIV RT by analyzing the biochemical and structural properties of these RT fidelity mutants.
- Role of mutation synthesis by HIV RT in viral evolution and escape: By using HIV containing RT mutants with altered fidelity we are studying the relationships between the replicational fidelity of HIV RT and viral evolution and escape. We are measuring accumulation of mutations and the rate of emerging drug resistant mutations during the course of viral passages with mutant and wild type viruses.
- HIV-1 Infection and dNTP biosynthesis: Using a highly sensitive dNTP assay, we recently observed that the cellular dNTP concentration of human macrophages is 50~100 times lower than that of the activated CD4+ T cells. We hypothesize that the HIV-1 infection may activate the dNTP biosynthesis, which can enhance viral replication and infectivity, particularly in non-dividing/terminally differentiated cells, macrophages and microglia. This project leads us to understand the status of cellular dNTPs which compete with nucleoside HIV-1 RT inhibitors during the HIV-1 therapy.
- Role of avian
flu RNA polymerase kinetics and fidelity in viral genomic mutagenesis,
evolution and host species change:
Genetic drift in influenza viruses is responsible for antigenic changes
in hemagglutinin and neuraminidase proteins and is likely responsible
for the ability of the current H5N1 avian influenza species to make the
host species transition to humans, with fatal consequences.
Genetic drift implicates the viral replication machinery as
mechanistically
involved in this process. The viral replication machinery must be capable of frequent mutation synthesis and massive viral replication in order to generate viral quasi-species capable of making this host specificity switch. Our laboratory has initiated a series of projects involving biochemical analysis and reverse genetic approaches aimed at understanding the involvement of avian influenza virus RNA polymerase kinetics and error rates in viral genetics and evolution. - Targeting PI3K/Aky cell survival pathway to eradicate long-living macrophage and microglia HIV-1 reservoirs in brain: HIV-1 infects microglia and macrophages in brain at early stage of viral infection and replicates to the end of the AIDS phase by establishing long-living HIV-1 reservoirs. We recently identified cellular mechanism hijacked by HIV-1 which extends life span of the infected macrophages and establish long-living viral reservoirs in brain. This pathway, PI3K/Akt cell survival pathway, is activated by HIV-1 infection, more specifically expression of HIV-1 Tat protein. Interestingly, this pathway has been extensively studied in cancer biology and inhibitors blocking this pathway are currently available because the activation of the Pi3K/Akt pathway is commonly observed in many cancer cells. Our lab focuses on testing various PI3K/Akt inhibitors for their anti-HIV effect by inducing cell death of long-living HIV-1 reservoir cell types such as macrophages and microglia.
- Recent Publications
- Bimber BN, Chugh P, Giorgi EE, Kim B, Almudevar A, Dewhurst S, O'Connor DH, Lee HY Nef gene evolution from a single transmitted strain in acute SIV infection. Retrovirology. 2009 Jun 8;6(1):57. [Epub ahead of print]
Skasko M, Diamond TL, Kim B Mechanistic Variations among Reverse Transcriptases of Simian Immunodeficiency Virus Variants Isolated from African Green Monkeys. Biochemistry. 2009 May 1. [Epub ahead of print]
Bradel-Tretheway BG, Kelley Z, Chakraborty-Sett S, Takimoto T, Kim B, Dewhurst S The human H5N1 influenza A virus polymerase complex is active in vitro over a broad range of temperatures, in contrast to the WSN complex, and this property can be attributed to the PB2 subunit. J Gen Virol. 2008 Dec;89(Pt 12):2923-32
Santos-Velazquez J, Kim B Deoxynucleoside triphosphate incorporation mechanism of foamy virus (FV) reverse transcriptase: implications for cell tropism of FV. J Virol. 2008 Aug;82(16):8235-8 - Skasko M, Kim B Compensatory role of human immunodeficiency virus central polypurine tract sequence in kinetically disrupted reverse transcription. J Virol. 2008 Aug;82(15):7716-20
- Gao L, Hanson MN, Balakrishnan M, Boyer PL, Roques BP, Hughes SH, Kim B, Bambara RA Apparent defects in processive DNA synthesis, strand transfer, and primer elongation of M184 mutants of HIV-1 reverse transcriptase derive solely from a dNTP utilization defect." J Biol Chem. 2008 Apr 4;283(14):9196-205
- Jamburuthugoda VK, Santos-Velazquez JM, Skasko M, Operario DJ, Purohit V, Chugh P, Szymanski EA, Wedekind JE, Bambara RA, Kim B " Reduced dNTP binding affinity of 3TC-resistant M184I HIV-1 reverse transcriptase variants responsible for viral infection failure to macrophage." J Biol Chem. 2008 Apr 4;283(14):9206-16
- Chugh P, Bradel-Tretheway B, Monteiro-Filho CM, Planelles V, Maggirwar SB, Dewhurst S, Kim B Akt inhibitors as an HIV-1 infected macrophage-specific anti-viral therapy.Retrovirology. 2008;5:11
- Purohit V, Roques BP, Kim B, Bambara RA. "Mechanisms that prevent template inactivation by HIV-1 reverse transcriptase RNase H cleavages." J Biol Chem. 2007 Mar 2;
- Matamoros T, Kim B, Menéndez-Arias L. "Mechanistic insights into the role of Val75 of HIV-1 reverse transcriptase in misinsertion and mispair extension fidelity of DNA synthesis." J Mol Biol. 2008 Feb 1;375(5):1234-48. Epub 2007 Nov 17
- Mock DJ, Chugh P, Kim B, Pröschel C, Dietrich J, Strathmann F, Blumberg BM, Mayer-Pröschel M "Characterization of specific HHV-6 and cell cycle genes implicated in virus-mediated G1/S cell-cycle arrest of glial precursors." Retrovirology. 2006 Dec 21;3 Suppl 1:S65.
- Andersen JL, Dehart JL,
Zimmerman ES, Ardon O, Kim B, Jacquot G, Benichou S, Planelles V.
"HIV-1 Vpr-Induced Apoptosis Is Cell Cycle Dependent and Requires Bax but Not ANT."
PLoS Pathog. 2006 Dec 1;2(12):e127 - Chugh P, Fan S, Planelles V, Maggirwar SB, Dewhurst S, Kim B "Infection of Human Immunodeficiency Virus and Intracellular Viral Tat Protein Exert a Pro-survival Effect in a Human Microglial Cell Line." J Mol Biol. 2006 Nov 10;
- Darwin J. Operario, Mini Balakrishnan, Robert A. Bambara, and Baek Kim "Reduced dNTP interaction of human immunodeficiency virus type 1 reverse transcriptase promotes strand transfer" J. Biol. Chem., Aug 2006; doi:10.1074/jbc.M604665200
- Jamburuthugoda VK, Chugh P, Kim B Modification of human immunodeficiency virus type 1 reverse transcriptase to target cells with elevated cellular dntp concentrations. J Biol Chem. 2006 May 12;281(19):13388-95
- Purohit V, Balakrishnan M, Kim B, Bambara RA (2005, in press) Evidence that HIV-1 reverse transcriptase employs the DNA 3' end-directed primary/secondary RNase H cleavage mechanism during synthesis and strand transfer. J Biol Chem 280(49): 40534-43.
- Jamburuthugoda VK, Guo D, Wedekind JE, and Kim B (2005) Kinetic Evidence for Interaction of Human Immunodeficiency Virus Type 1 Reverse Transcriptase with the 3'-OH of the Incoming dTTP Substrate. Biochemistry 44(31):10635-43
- Operario DJ, Reynolds HM, and Kim B (2005). Enzymatic Comparison of DNA polymerase activities of Feline Immunodeficiency Virus and Feline Leukemia Virus. Virology. 335(1):106-21.
- Skasko M, Weiss KK, Reynolds HM, Jamburuthugoda V, Lee K, and Kim B (2005) Mechanistic Differences in RNA dependent DNA polymerization and Fidelity between MuLV and HIV-1 Reverse Transcriptases. J. Biol. Chem. 280(13):12190-200.
- Dehart JL, Andersen JL, Zimmerman ES, Ardon O, An DS, Blackett J, Baek Kim, Planelles V. (2005) The ataxia telangiectasia-mutated and Rad3-related protein is dispensable for retroviral integration. J. Virol. 2005 79(3):1389-96.
- Weiss, K. K., Chen, R., Skasko, M., Reynolds, H. M., Lee, K., Bambara, R. A., Mansky, L. M., and Kim, B. (2004) A Role for dNTP Binding of Human Immunodeficiency Virus Type 1 Reverse Transcriptase in Viral Mutagenesis,Biochemistry 43, 4490-4500.
- Roshal, M., Kim, B., Zhu, Y., Nghiem, P., and Planelles, V. (2003) Activation of the ATR-mediated DNA damage response by the HIV-1 viral protein R,J Biol Chem 278, 25879-86.
- Diamond, T. L., Souroullas, G., Weiss, K. K., Lee, K. Y., Bambara, R. A., Dewhurst, S., and Kim, B. (2003) Mechanistic understanding of an altered fidelity simian immunodeficiency virus reverse transcriptase mutation, V148I, identified in a pig-tailed macaque,J Biol Chem 278, 29913-24.
- Weiss, K. K., Bambara, R. A., and Kim, B. (2002) Mechanistic role of residue Gln151 in error prone DNA synthesis by human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). Pre-steady state kinetic study of the Q151N HIV-1 RT mutant with increased fidelity,J Biol Chem 277, 22662-9.
- Malboeuf, C. M., Isaacs, S. J., Tran, N. H., and Kim, B. (2001) Thermal effects on reverse transcription: improvement of accuracy and processivity in cDNA synthesis,Biotechniques 30, 1074-8, 1080, 1082, passim.
- Diamond, T. L., Kimata, J., and Kim, B. (2001) Identification of a simian immunodeficiency virus reverse transcriptase variant with enhanced replicational fidelity in the late stage of viral infection,J Biol Chem 276, 23624-31.
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