Baek Kim
| Title | Professor |
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| Institution | School of Medicine and Dentistry |
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| Department | Microbiology and Immunology |
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| Address | University of Rochester Medical Center
School of Medicine and Dentistry
601 Elmwood Ave, Box 672
Rochester NY 14642
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| 1978 |
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| 1981 | Full Scholarship Award | Hyundai Corp | | 1993 |
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| Best Thesis of the Year | Department of Biochemistry | | 1995 |
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| Young investigator award, Methods for Basic Research and Drug Discovery | International Conference on Combinatorial Library |
1. Research Projects in Progress
(A)
Enzymology of HIV-1 reverse transcriptase: Molecular evolution and mutagenesis of lentiviruses
HIV-1 reverse transcriptase is the most error-prone DNA polymerases among known replication DNA polymerases. Our research primarily focuses on mechanistic and structural understanding of the error-prone active site of HIV-1 RT. Other RTs with high fidelity such as MuLV RT is also studied for identifying molecular elements that contribute to the fidelity difference between HIV-1 and MuLV RTs. For this study we employ both pre-steady and steady state kinetic analyses as well as other well established fidelity assays such as M13 lacZ? forward mutation assay and gel-based misincorporation assay. Next, we also focus on the contribution of the RT fidelity in HIV-1 genomic mutagenesis, evolution and escape using various virological methodologies. This study is currently being supported by NIH R01 AI049781.
(B)
Modification of viral DNA polymerases for designing new oncolytic viruses: Based on our HIV-1 RT studies, we recently established a new concept for constructing oncolytic viruses. The DNA polymerase mutants with reduced dNTP binding affinity are active only at the high dNTP concentrations. In addition, it has been well-established that all cancer cells with uncontrolled cell cycle have highly elevated dNTP concentrations than normal cells due to their fast cell division phenotype. We hypothesize that adenovirus containing mutant DNA polymerase with reduced dNTP binding affinity replicates specifically in the cells with elevated dNTP concentrations such as cancer cells. We employ thermo-stable Pfu DNA polymerase, which, together with adenovirus DNA polymerase, belongs to the same alpha-like DNA polymerase family to screen mutant with reduced dNTP binding affinity. This study is being supported by NCI CA122213 (Pancreatic cancer) and DOD BC060381 (breast cancer).
(C) HIV-1 and macrophage reservoirs: Research Activities on understanding roles of HIV-1 Tat protein in 1) DNA damage signal induction, 2) activation of dNTP biosynthesis, and 3) viral reverse transcription kinetics in human macrophages. These research projects focus on testing the Vpr functions as a HIV target. This research activity includes collaborations with Dr. Stephen Dewhurst and Dr. Vicente Planelles (University of Utah). The R01 support for this project was recently reviewed and approved for funding (AI077401).
(D) Recombination and HIV-1 evolution: Research activities on identifying molecular determinants of lentiviral recombination. These studies focus on roles of RT processivity, viral cis-acting sequences (secondary structures) and RT polymerase kinetics in viral recombination frequency. These research activities include collaborations with Dr. Robert A. Bambara (Baek Kim, Co-PI, NIH GM049573)
(E) Fidelity of avian influenza virus RNA polymerases: Research activities on examining enzymatic fidelity of avian and H5N1 influenza RNA polymerases, and its role in viral evolution and host adaptation. This project is a part of NIH contract awarded to NY Influenza Center of Excellence (Co-PI, NIH HHSN26620077778C).
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Amie SM, Noble E, Kim B. Intracellular nucleotide levels and the control of retroviral infections. Virology. 2013 Feb 20; 436(2):247-54.
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St Gelais C, de Silva S, Amie SM, Coleman CM, Hoy H, Hollenbaugh JA, Kim B, Wu L. SAMHD1 restricts HIV-1 infection in dendritic cells (DCs) by dNTP depletion, but its expression in DCs and primary CD4+ T-lymphocytes cannot be upregulated by interferons. Retrovirology. 2012; 9:105.
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Joh EH, Hollenbaugh JA, Kim B, Kim DH. Pleckstrin homology domain of akt kinase: a proof of principle for highly specific and effective non-enzymatic anti-cancer target. PLoS One. 2012; 7(11):e50424.
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White TE, Brandariz-Nuñez A, Carlos Valle-Casuso J, Amie S, Nguyen L, Kim B, Brojatsch J, Diaz-Griffero F. Contribution of SAM and HD domains to retroviral restriction mediated by human SAMHD1. Virology. 2013 Feb 5; 436(1):81-90.
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Baldauf HM, Pan X, Erikson E, Schmidt S, Daddacha W, Burggraf M, Schenkova K, Ambiel I, Wabnitz G, Gramberg T, Panitz S, Flory E, Landau NR, Sertel S, Rutsch F, Lasitschka F, Kim B, König R, Fackler OT, Keppler OT. SAMHD1 restricts HIV-1 infection in resting CD4(+) T cells. Nat Med. 2012 Nov; 18(11):1682-9.
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Perez JT, Zlatev I, Aggarwal S, Subramanian S, Sachidanandam R, Kim B, Manoharan M, Tenoever BR. A Small-RNA Enhancer of Viral Polymerase Activity. J Virol. 2012 Dec; 86(24):13475-85.
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Hofmann H, Logue EC, Bloch N, Daddacha W, Polsky SB, Schultz ML, Kim B, Landau NR. The Vpx Lentiviral Accessory Protein Targets SAMHD1 for Degradation in the Nucleus. J Virol. 2012 Dec; 86(23):12552-60.
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Noble E, Cox A, Deval J, Kim B. Endonuclease substrate selectivity characterized with full-length PA of influenza A virus polymerase. Virology. 2012 Nov 10; 433(1):27-34.
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Capella C, Beltejar MJ, Brown C, Fong V, Daddacha W, Kim B, Dewhurst S. Selective Modification of Adenovirus Replication Can Be Achieved through Rational Mutagenesis of the Adenovirus Type 5 DNA Polymerase. J Virol. 2012 Oct; 86(19):10484-93.
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Gavegnano C, Kennedy EM, Kim B, Schinazi RF. The Impact of Macrophage Nucleotide Pools on HIV-1 Reverse Transcription, Viral Replication, and the Development of Novel Antiviral Agents. Mol Biol Int. 2012; 2012:625983.
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Lahouassa H, Daddacha W, Hofmann H, Ayinde D, Logue EC, Dragin L, Bloch N, Maudet C, Bertrand M, Gramberg T, Pancino G, Priet S, Canard B, Laguette N, Benkirane M, Transy C, Landau NR, Kim B, Margottin-Goguet F. SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates. Nat Immunol. 2012; 13(6):621.
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Kim B, Nguyen LA, Daddacha W, Hollenbaugh JA. Tight Interplay among SAMHD1 Protein Level, Cellular dNTP Levels, and HIV-1 Proviral DNA Synthesis Kinetics in Human Primary Monocyte-derived Macrophages. J Biol Chem. 2012 Jun 22; 287(26):21570-4.
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Mock DJ, Hollenbaugh JA, Daddacha W, Overstreet MG, Lazarski CA, Fowell DJ, Kim B. Leishmania Induces Survival, Proliferation and Elevated Cellular dNTP Levels in Human Monocytes Promoting Acceleration of HIV Co-Infection. PLoS Pathog. 2012 Apr; 8(4):e1002635.
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Kennedy EM, Amie SM, Bambara RA, Kim B. Frequent Incorporation of Ribonucleotides during HIV-1 Reverse Transcription and Their Attenuated Repair in Macrophages. J Biol Chem. 2012 Apr 20; 287(17):14280-8.
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Lahouassa H, Daddacha W, Hofmann H, Ayinde D, Logue EC, Dragin L, Bloch N, Maudet C, Bertrand M, Gramberg T, Pancino G, Priet S, Canard B, Laguette N, Benkirane M, Transy C, Landau NR, Kim B, Margottin-Goguet F. SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates. Nat Immunol. 2012; 13(3):223-8.
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Macdonald LA, Aggarwal S, Bussey KA, Desmet EA, Kim B, Takimoto T. Molecular interactions and trafficking of influenza A virus polymerase proteins analyzed by specific monoclonal antibodies. Virology. 2012 Apr 25; 426(1):51-9.
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Van Cor-Hosmer SK, Daddacha W, Kelly Z, Tsurumi A, Kennedy EM, Kim B. The impact of molecular manipulation in residue 114 of human immunodeficiency virus type-1 reverse transcriptase on dNTP substrate binding and viral replication. Virology. 2012 Jan 20; 422(2):393-401.
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Nguyen LA, Daddacha W, Rigby S, Bambara RA, Kim B. Altered strand transfer activity of a multiple-drug-resistant human immunodeficiency virus type 1 reverse transcriptase mutant with a dipeptide fingers domain insertion. J Mol Biol. 2012 Jan 13; 415(2):248-62.
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Aggarwal S, Dewhurst S, Takimoto T, Kim B. Biochemical impact of the host adaptation-associated PB2 E627K mutation on the temperature-dependent RNA synthesis kinetics of influenza A virus polymerase complex. J Biol Chem. 2011 Oct 7; 286(40):34504-13.
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Muchiri JM, Rigby ST, Nguyen LA, Kim B, Bambara RA. HIV-1 reverse transcriptase dissociates during strand transfer. J Mol Biol. 2011 Sep 23; 412(3):354-64.
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Kim Y, Hollenbaugh JA, Kim DH, Kim B. Novel PI3K/Akt inhibitors screened by the cytoprotective function of human immunodeficiency virus type 1 Tat. PLoS One. 2011; 6(7):e21781.
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Hollenbaugh JA, Munger J, Kim B. Metabolite profiles of human immunodeficiency virus infected CD4+ T cells and macrophages using LC-MS/MS analysis. Virology. 2011 Jul 5; 415(2):153-9.
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Bussey KA, Desmet EA, Mattiacio JL, Hamilton A, Bradel-Tretheway B, Bussey HE, Kim B, Dewhurst S, Takimoto T. PA residues in the 2009 H1N1 pandemic influenza virus enhance avian influenza virus polymerase activity in mammalian cells. J Virol. 2011 Jul; 85(14):7020-8.
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Noble E, Mathews DH, Chen JL, Turner DH, Takimoto T, Kim B. Biophysical analysis of influenza A virus RNA promoter at physiological temperatures. J Biol Chem. 2011 Jul 1; 286(26):22965-70.
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Kennedy EM, Daddacha W, Slater R, Gavegnano C, Fromentin E, Schinazi RF, Kim B. Abundant non-canonical dUTP found in primary human macrophages drives its frequent incorporation by HIV-1 reverse transcriptase. J Biol Chem. 2011 Jul 15; 286(28):25047-55.
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Kennedy EM, Gavegnano C, Nguyen L, Slater R, Lucas A, Fromentin E, Schinazi RF, Kim B. Ribonucleoside triphosphates as substrate of human immunodeficiency virus type 1 reverse transcriptase in human macrophages. J Biol Chem. 2010 Dec 10; 285(50):39380-91.
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Lucas A, Kim Y, Rivera-Pabon O, Chae S, Kim DH, Kim B. Targeting the PI3K/Akt cell survival pathway to induce cell death of HIV-1 infected macrophages with alkylphospholipid compounds. PLoS One. 2010; 5(9).
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Van Cor-Hosmer SK, Daddacha W, Kim B. Mechanistic interplay among the M184I HIV-1 reverse transcriptase mutant, the central polypurine tract, cellular dNTP concentrations and drug sensitivity. Virology. 2010 Oct 25; 406(2):253-60.
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Aggarwal S, Bradel-Tretheway B, Takimoto T, Dewhurst S, Kim B. Biochemical characterization of enzyme fidelity of influenza A virus RNA polymerase complex. PLoS One. 2010; 5(4):e10372.
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Bussey KA, Bousse TL, Desmet EA, Kim B, Takimoto T. PB2 residue 271 plays a key role in enhanced polymerase activity of influenza A viruses in mammalian host cells. J Virol. 2010 May; 84(9):4395-406.
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Kennedy EM, Hergott C, Dewhurst S, Kim B. The mechanistic architecture of thermostable Pyrococcus furiosus family B DNA polymerase motif A and its interaction with the dNTP substrate. Biochemistry. 2009 Dec 1; 48(47):11161-8.
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Skasko M, Diamond TL, Kim B. Mechanistic variations among reverse transcriptases of simian immunodeficiency virus variants isolated from African green monkeys. Biochemistry. 2009 Jun 16; 48(23):5389-95.
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Bimber BN, Chugh P, Giorgi EE, Kim B, Almudevar AL, Dewhurst S, O'Connor DH, Lee HY. Nef gene evolution from a single transmitted strain in acute SIV infection. Retrovirology. 2009; 6:57.
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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.
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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.
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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.
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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.
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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 in macrophage. J Biol Chem. 2008 Apr 4; 283(14):9206-16.
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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 Met-184 mutants of HIV-1 reverse transcriptase derive solely from a dNTP utilization defect. J Biol Chem. 2008 Apr 4; 283(14):9196-205.
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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.
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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 Apr 27; 282(17):12598-609.
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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; 2(12):e127.
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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. 2007 Feb 9; 366(1):67-81.
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Operario DJ, Balakrishnan M, Bambara RA, Kim B. Reduced dNTP interaction of human immunodeficiency virus type 1 reverse transcriptase promotes strand transfer. J Biol Chem. 2006 Oct 27; 281(43):32113-21.
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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.
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Purohit V, Balakrishnan M, Kim B, Bambara RA. 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. 2005 Dec 9; 280(49):40534-43.
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Jamburuthugoda VK, Guo D, Wedekind JE, Kim B. Kinetic evidence for interaction of human immunodeficiency virus type 1 reverse transcriptase with the 3'-OH of the incoming dTTP substrate. Biochemistry. 2005 Aug 9; 44(31):10635-43.
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Operario DJ, Reynolds HM, Kim B. Comparison of DNA polymerase activities between recombinant feline immunodeficiency and leukemia virus reverse transcriptases. Virology. 2005 Apr 25; 335(1):106-21.
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Dehart JL, Andersen JL, Zimmerman ES, Ardon O, An DS, Blackett J, Kim B, Planelles V. The ataxia telangiectasia-mutated and Rad3-related protein is dispensable for retroviral integration. J Virol. 2005 Feb; 79(3):1389-96.
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Skasko M, Weiss KK, Reynolds HM, Jamburuthugoda V, Lee K, Kim B. Mechanistic differences in RNA-dependent DNA polymerization and fidelity between murine leukemia virus and HIV-1 reverse transcriptases. J Biol Chem. 2005 Apr 1; 280(13):12190-200.
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Diamond TL, Roshal M, Jamburuthugoda VK, Reynolds HM, Merriam AR, Lee KY, Balakrishnan M, Bambara RA, Planelles V, Dewhurst S, Kim B. Macrophage tropism of HIV-1 depends on efficient cellular dNTP utilization by reverse transcriptase. J Biol Chem. 2004 Dec 3; 279(49):51545-53.
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Weiss KK, Chen R, Skasko M, Reynolds HM, Lee K, Bambara RA, Mansky LM, Kim B. A role for dNTP binding of human immunodeficiency virus type 1 reverse transcriptase in viral mutagenesis. Biochemistry. 2004 Apr 20; 43(15):4490-500.
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Roshal M, Kim B, Zhu Y, Nghiem P, Planelles V. Activation of the ATR-mediated DNA damage response by the HIV-1 viral protein R. J Biol Chem. 2003 Jul 11; 278(28):25879-86.
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Diamond TL, Souroullas G, Weiss KK, Lee KY, Bambara RA, Dewhurst S, Kim B. Mechanistic understanding of an altered fidelity simian immunodeficiency virus reverse transcriptase mutation, V148I, identified in a pig-tailed macaque. J Biol Chem. 2003 Aug 8; 278(32):29913-24.
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Chey WY, Chang CH, Pan HJ, Chang C, Kim BM, Park IS, Chang TM. Evidence on the presence of secretin cells in the gastric antral and oxyntic mucosa. Regul Pept. 2003 Mar 28; 111(1-3):183-90.
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Weiss KK, Bambara RA, Kim B. 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. 2002 Jun 21; 277(25):22662-9.
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Patel D, Frelinger J, Goudsmit J, Kim B. In vitro assay for site-specific proteases using bead-attached GFP substrate. Biotechniques. 2001 Nov; 31(5):1194, 1196, 1198 passim.
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Luo Y, Pfuetzner RA, Mosimann S, Paetzel M, Frey EA, Cherney M, Kim B, Little JW, Strynadka NC. Crystal structure of LexA: a conformational switch for regulation of self-cleavage. Cell. 2001 Sep 7; 106(5):585-94.
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Malboeuf CM, Isaacs SJ, Tran NH, Kim B. Thermal effects on reverse transcription: improvement of accuracy and processivity in cDNA synthesis. Biotechniques. 2001 May; 30(5):1074-8, 1080, 1082, passim.
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Diamond TL, Kimata J, Kim B. Identification of a simian immunodeficiency virus reverse transcriptase variant with enhanced replicational fidelity in the late stage of viral infection. J Biol Chem. 2001 Jun 29; 276(26):23624-31.
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Weiss KK, Isaacs SJ, Tran NH, Adman ET, Kim B. Molecular architecture of the mutagenic active site of human immunodeficiency virus type 1 reverse transcriptase: roles of the beta 8-alpha E loop in fidelity, processivity, and substrate interactions. Biochemistry. 2000 Sep 5; 39(35):10684-94.
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Kim B, Ayran JC, Sagar SG, Adman ET, Fuller SM, Tran NH, Horrigan J. New human immunodeficiency virus, type 1 reverse transcriptase (HIV-1 RT) mutants with increased fidelity of DNA synthesis. Accuracy, template binding, and processivity. J Biol Chem. 1999 Sep 24; 274(39):27666-73.
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Kim B, Hathaway TR, Loeb LA. Fidelity of mutant HIV-1 reverse transcriptases: interaction with the single-stranded template influences the accuracy of DNA synthesis. Biochemistry. 1998 Apr 28; 37(17):5831-9.
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Choi JI, Schifferle RE, Yoshimura F, Kim BW. Capsular polysaccharide-fimbrial protein conjugate vaccine protects against Porphyromonas gingivalis infection in SCID mice reconstituted with human peripheral blood lymphocytes. Infect Immun. 1998 Jan; 66(1):391-3.
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Kim B. Genetic selection in Escherichia coli for active human immunodeficiency virus reverse transcriptase mutants. Methods. 1997 Aug; 12(4):318-24.
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Suzuki M, Christians FC, Kim B, Skandalis A, Black ME, Loeb LA. Tolerance of different proteins for amino acid diversity. Mol Divers. 1996 Oct; 2(1-2):111-8.
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Kim B, Hathaway TR, Loeb LA. Human immunodeficiency virus reverse transcriptase. Functional mutants obtained by random mutagenesis coupled with genetic selection in Escherichia coli. J Biol Chem. 1996 Mar 1; 271(9):4872-8.
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Kim B, Loeb LA. A screen in Escherichia coli for nucleoside analogs that target human immunodeficiency virus (HIV) reverse transcriptase: coexpression of HIV reverse transcriptase and herpes simplex virus thymidine kinase. J Virol. 1995 Oct; 69(10):6563-6.
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Kim B, Loeb LA. Human immunodeficiency virus reverse transcriptase substitutes for DNA polymerase I in Escherichia coli. Proc Natl Acad Sci U S A. 1995 Jan 31; 92(3):684-8.
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Blank A, Kim B, Loeb LA. DNA polymerase delta is required for base excision repair of DNA methylation damage in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 1994 Sep 13; 91(19):9047-51.
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Little JW, Kim B, Roland KL, Smith MH, Lin LL, Slilaty SN. Cleavage of LexA repressor. Methods Enzymol. 1994; 244:266-84.
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Kim B, Little JW. LexA and lambda Cl repressors as enzymes: specific cleavage in an intermolecular reaction. Cell. 1993 Jun 18; 73(6):1165-73.
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Kim B, Little JW. Dimerization of a specific DNA-binding protein on the DNA. Science. 1992 Jan 10; 255(5041):203-6.
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