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    Experimental Pathology
    7117 WMB, 101 Woodruff Circle
    Atlanta, GA 30322
    404 712-9005 Phone

    For an expert Pathology consultation,
    or to send a specimen, call:

    1-404-712-5947


    William Lewis, MD

    Cardiovascular Biology
    HIV Pathogenesis
    Cardiac Pathology

    Professor
    Pathology & Laboratory Medicine


    Pathology Faculty Photo

    Other Appointments/Positions

    Professor (tenured), Pathology, Director, Cardiovascular Pathology, Emory University School of Medicine, Atlanta GA


    Pathology Division(s):
    Anatomic Pathology
    Experimental Pathology


    Email Address:
    wlewis@emory.edu


    Education:

    B.S.   University of Michigan, Ann Arbor, MI (Zoology), 1968 - 1971

    M.D.   Boston University School of Medicine (M.D.), 1971 - 1975



    Research Interests:

    - Mitochondrial DNA replication in disease: AIDS, congestive heart failure, hepatitis, renal failure
    One classic biological teaching is that mitochondria are the "powerhouses of the cell", particularly in tissues that require significant energy, like heart, liver and muscle. The focus of the Lewis lab is the diverse effects of toxins on mitochondria structure and function. The primary focus is the untoward mitochondrial effects of a class of drugs called nucleoside reverse transcriptase inhibitors (NRTI) used to treat HIV infection, that are known to inhibit mitochondrial (mt-) DNA replication in vitro. These drugs are toxic to various tissues including heart, skeletal muscle, liver and kidney. Our overall goals are to (1) define the molecular mechanisms of how NRTIs change the abundance of precursors for mtDNA replication in vivo (2) define the effects of active NRTI triphosphates on the mitochondrial replicon in vivo (3) define the effects of specific polymerase mutants on the replication of mtDNA in vivo and (4) define the effects of the mtDNA template itself on its replication in vivo. The approach taken employs tissue specific targeting of genes involved in the processes and evaluation of structural and functional defects that result using state of the art biochemical, molecular, physiological, and pathological approaches. Conditional, tissue specific targeting also is addressed. The direct clinical benefits of these studies are twofold (1) the toxicity of important compounds is defined so that better therapeutics can be designed and administered and (2) mechanisms of organ specific changes in HIV disease and related illnesses are elucidated.



    Clinical Focus:

    Cardiovascular Disease, Heart Transplantation, HIV effects on the cardiovascular system


    Honors / Awards:

    Alpha Omega Alpha

    , 2006

    Chartered Member, Contractility Congestive heart failure SS NIH, CSR, 2003-2007

    Clinician-Investigator Award, 2001-2004

    Honorary, Member, Italian Society, 2000

    Award of Merit, Society for Cardiology, 1995

    Mentor, Commonwealth Fund Scho, 1989-1990

    Mount Sinai Journal of Medicine, 1984-1985

    Sigma XI

    , 1984

    Recipient, Clinical Investigation, 1982-1987

    Specialty Boards:

    1983 Diplomate Anatomic and Clinical Pathology


    Selected Publications:

    Published and Accepted Research Articles -

    JJ Kohler, SH Hosseini, E Green, A Hoying-Brandt, CP Haase, R Russ, J Srivastava, K Ivey, T Ludaway, V Kapoor, R Santoianni, A Saada, O Elpeleg and W Lewis. "Cardiac targeted transgenic mutant mitochondrial enzymes: mtDNA antiretroviral toxicity and cardiomyopathy". Cardiovasc Toxicol 8(2):57-69. (2008). http://www.ncbi.nlm.nih.gov/pubmed/18446447


    Kohler JJ, Hosseini SH, and Lewis W. "Mitochondrial DNA impairment in nucleoside reverse transcriptase inhibitor-associated cardiomyopathy." Chem Res Toxicol. May; 21(5):990-6, (2008). http://www.ncbi.nlm.nih.gov/pubmed/18393452


    Kohler, J.J. and W. Lewis, "A brief overview of mechanisms of mitochondrial toxicity from NRTIs. " Environmental & Molecular Mutagenesis, 48(3-4):p166-72, (2007). http://www.ncbi.nlm.nih.gov/pubmed/16758472


    SH Hosseini, JJ Kohler, CP Haase, N Tioleco, T Stuart, E Keebaugh, T Ludaway, R Russ, R Long, L Wang S Eriksson and W Lewis. "Targeted transgenic overexpression of mitochondrial thymidine kinase (TK2) regulates mtDNA and mitochondrial polypeptide abundance". AmJPath 170:865-874, (2007). http://www.ncbi.nlm.nih.gov/pubmed/17322372


    Lewis,W., et al., "Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase gamma." Lab Investigation, 87(4):p. 326-35, (2007). http://www.ncbi.nlm.nih.gov/pubmed/17310215


    Lewis, William, Kohler, James J., Hosseini, Seyed H, Haase, Chad P., Copeland, William C., Bienstock, Rachelle, J., Ludaway, Tomika, McNaught, Jamie, Russ, Rodney, Stuart, Tamie and Santioianni, Robert. "Antiretroviral nucleosides, deoxynucleotide carrier and mitochondrial DNA: evidence supporting the DNA pol gamma hypothesis" AIDS 20: 675-684.(2006). http://www.ncbi.nlm.nih.gov/pubmed/16514297


    Lewis, William "Nucleoside reverse transcriptase inhibitors, mitochondrial DNA and AIDS Therapy" Antiviral Therapy 10: (Suppl 2) M13-M27. (2005). http://www.ncbi.nlm.nih.gov/pubmed/16152703


    Lewis, William, Yoon K. Miller, Chad P. Haase, Tomika Ludaway, Jamie McNaught, Rodney Russ, Jeffrey Steltzer, Andrew Folpe, Robert Long and John Oshinski. "HIV viral protein R causes atrial cardiomyocyte mitosis, mesenchymal tumor, dysrhythmias, and heart failure." Laboratory Investigation 85:182-192 (2005). http://www.ncbi.nlm.nih.gov/pubmed/15608661


    Lewis, William, Haase, Chad P., Miller, Yoon Kim,; Ferguson, Brandy; Ludaway, Tomika; McNaught, Jamie; Russ, Rodney; Steltzer, Jeffrey; Long, Robert; Fieramonte, Giuseppe, and Palmieri, Ferdinando: "Transgenic expression of the deoxynucleotide carrier causes mitochondrial damage that is enhanced by NRTIs for AIDS" Laboratory Investigation, 85:972-981. (2005). http://www.ncbi.nlm.nih.gov/pubmed/15951836


    Cheng, Lihong, Ding, Guoliang, Qin, Qianhong, Huang, Yao, Lewis, William, He, Nu, Evans, Ronald M., Schneider, Michael D., Brako, Florence A., Xiao, Yan Chen, Yuqing E. and Yang, Qinglin. "Cardiomyocyte-restricted peroxisome proliferator-activated receptor d perturbs myocardial fatty acid oxidation and leads to cardiomyopathy." Nature Medicine 10: 1245-1250. (2004). http://www.ncbi.nlm.nih.gov/pubmed/15475963


    Lewis, William: "Cardiomyopathy, nucleoside reverse transcriptase inhibitors and mitochondria are linked through AIDS and its therapy." Mitochondrion 4:141-152. (2004). http://www.ncbi.nlm.nih.gov/pubmed/16120379


    Velsor, Leonard W., Kovacevic, Miro, Goldstein, Mark, Leitner, Heather M., Lewis, William, and Day, Brian J. "Mitochondrial Oxidative Stress in Human Hepatoma Cells Exposed to Stavudine". Toxicology and Applied Pharmacology. (2004). http://www.ncbi.nlm.nih.gov/pubmed/15289086


    Day, Brian J. and Lewis, William: "Oxidative Stress in NRTI-Induced Toxicity: Evidence from Clinical Experience and Experiments in vitro and in vivo." Cardiovascular Toxicology 4:207-216. (2004). http://www.ncbi.nlm.nih.gov/pubmed/15470269


    Lewis, William: "Mitochondrial dysfunction and nucleoside reverse transcriptase inhibitor therapy: experimental clarifications and persistent clinical questions." Antiviral Res 58:189-197. (2003). http://www.ncbi.nlm.nih.gov/pubmed/14526384


    Sutliff; Roy L., Haase, Chad, Russ, Rodney, Hoit, Brian D., Morris, Randal, Norman, Andrew B., and Lewis, William: "Cocaine increases mortality and cardiac mass in a murine transgenic model of Acquired Immune Deficiency Syndrome". Laboratory Investigation 83:983-989. (2003). http://www.ncbi.nlm.nih.gov/pubmed/12861038


    Lewis, William, Day, Brian and Copeland, William: "Mitochondrial toxicity from nucleoside reverse transcriptase inhibitors: an integrated cellular perspective." Nature Drug Discovery 2:812-822. (2003). http://www.ncbi.nlm.nih.gov/pubmed/12861038


    Lewis, William: "Use of transgenic mouse in models of AIDS cardiomyopathy" AIDS (supl 1) S36-S45. (2003). http://www.ncbi.nlm.nih.gov/pubmed/12870529


    Lewis, William: "Mitochondrial DNA replication, nucleoside reverse transcriptase inhibitors, and AIDS cardiomyopathy" Prog Cardiovasc Dis 45:305-318. (2003). http://www.ncbi.nlm.nih.gov/pubmed/12638094


    Raidel, Scott, Haase, Chad, Jansen, Natalie R., Russ, Rodney B., Sutliff, Roy L., Velsor, Leonard W., Day, Brian J., Hoit, Brian D., Samarel, Allen M. and Lewis, William. "Targeted myocardial transgenic expression of HIV Tat causes cardiomyopathy and mitochondrial damage" Amer J Physiol 282: H1672-H1678. (2002). http://www.ncbi.nlm.nih.gov/pubmed/11959630


    Muth, James N., Bodi, Ilona, Lewis, William, Varadi, Gyula, and Schwartz, Arnold. "A Ca2+-Dependent transgenic model of cardiac hypertrophy" Circulation 103:140-147. (2001). http://www.ncbi.nlm.nih.gov/pubmed/11136699


    Lewis, William, Copeland, William, and Day, Brian. "Mitochondrial DNA depletion, oxidative stress, and mutation: mechanisms of dysfunction from nucleoside reverse transcriptase inhibitors." Laboratory Investigation 81:777-790. (2001).http://www.ncbi.nlm.nih.gov/pubmed/11406640


    Lewis, William: "Cardiomyopathy in AIDS: a pathophysiological perspective." Progress Cardiovasc Disease 43:151-170. (2000). http://www.ncbi.nlm.nih.gov/pubmed/11014331


    Lewis, William, Grupp, Ingrid, Grupp, G¿nter, Hoit, Brian, Morris, Randall, Samarel, Allen M., Bruggeman, Leslie, and Klotman, Paul. "Cardiac dysfunction occurs in the HIV-1 transgenic mouse treated with zidovudine." Laboratory Investigation 80:187-97. (2000). http://www.ncbi.nlm.nih.gov/pubmed/10701688


    Lewis, William: "Atherosclerosis in AIDS: potential pathogenetic roles of antiretroviral therapy and HIV". J Molec Cell Cardiol 32:2115-2129. (2000). http://www.ncbi.nlm.nih.gov/pubmed/11112988


    Tennant, Bud C., Baldwin, Betty H., Graham, Lou Ann, Ascenzi, Mary A., Rowland, Peter H., Torchov, Ilia A., Yeager, Amy E., Erb, Hollis N., Colacino, Joseph M., Lopez, Carlos, Engelhardt, Jeffrey A., Bowsher, Ronald R., Richardson, Frank C., Lewis, William, Cote, Paul J., Korba, Brent A., and Gerin, John G. "Antiviral activity and toxicity of fialuridine (FIAU) in the woodchuck model of Hepatitis B virus infection". Hepatology 28:179-191 (1998). http://www.ncbi.nlm.nih.gov/pubmed/9657111


    Lewis, William, Griniuviene, Brone, Tankersley, Kevin O. Levine, Eric S., Montione, Richard, Engelman, Laura, de Courten-Myers, Gabrielle, Ascenzi, Mary Hornbuckle, William E, Gerin, John G., and Tennant, Bud C.: "Depletion of mitochondrial DNA, destruction of mitochondria and accumulation of lipid droplets result from fialuridine treatment in woodchucks (Marmota monax)." Laboratory Investigation 76:77-87 (1997). http://www.ncbi.nlm.nih.gov/pubmed/9010451


    Lewis, William, Levine, Eric S., Griniuviene, Brone, Tankersley Kevin O., Sommadossi, Jean-Pierre, Watanabe, Kyoichi, Colacino, Joseph, and Perrino, Fred W. "Fialuridine and its metabolites inhibit DNA polymerase-g at sites of multiple adjacent analog incorporation, decrease mtDNA abundance, and cause mitochondrial structural defects in cultured hepatoblasts." Proc Natl Acad Sci (USA) 93:3592-3597 (1996). http://www.ncbi.nlm.nih.gov/pubmed/8622980


    Lewis, William and Dalakas, Marinos. "Mitochondrial toxicity of antiviral drugs." Nature Medicine 1:417-422 (1995). http://www.ncbi.nlm.nih.gov/pubmed/ 7585087


    Lewis, William, , Meyer, Ralph R., Simpson, James F., Colacino Joseph M., and Perrino, Fred W. "Mammalian DNA polymerases ¿, alpha, Beta, gamma, and delta incorporate fialuridine (FIAU) monophosphate into DNA and are inhibited competitively by FIAU triphosphate." Biochemistry 33:14620-14624 (1994). http://www.ncbi.nlm.nih.gov/pubmed/7981224


    Lewis, William, Simpson, James F., and Meyer, Ralph R. "Cardiac mitochondrial DNA polymerase ¿ is inhibited competitively and noncompetitively by phosphorylated zidovudine." Circulation Research 74:344-48 (1994). http://www.ncbi.nlm.nih.gov/pubmed/8293572


    Lewis, William and Grody, Wayne W.: "AIDS and the heart: review and consideration of pathogenetic mechanisms." Cardiovascular Pathology 1:53 64 (1992). doi:10.1016/1054-8807(92)90007-B


    Lewis, William; Gonzalez, Basilio; Chomyn Anne; and Papoian Thomas: "Zidovudine induces molecular, biochemical and ultrastructural changes in rat skeletal muscle mitochondria." Journal of Clinical Investigation 89:1354-1360 (1992). http://www.ncbi.nlm.nih.gov/pubmed/556193


    Lewin, David, d'Amati, Giulia, and Lewis, William. "Hypersensitivity myocarditis: findings in native and transplanted hearts" Cardiovascular Pathology 1:225-230 (1992). doi:10.1016/1054-8807(92)90029-N


    Grody, Wayne W.; Cheng, Lorna; and Lewis, William: "Infection of the heart by the human immunodeficiency virus". American Journal of Cardiology 66:203-206 (1990). http://www.ncbi.nlm.nih.gov/pubmed/2371952


    Lewis, William: "AIDS: Cardiac findings from 115 autopsies." Progress in Cardiovascular Disease XXXII:207-215 (1989). http://www.ncbi.nlm.nih.gov/pubmed/2530606


    Cammarosano, Carmine; and Lewis, William: "Cardiac lesions in acquired immune deficiency syndrome (AIDS): a postmortem study." Journal of the American College of Cardiology 5:703-706 (1985). http://www.ncbi.nlm.nih.gov/pubmed/3838661


    Book Chapters -

    Lewis, William, Dialogues in Cardiovascular Medicine; Vol. 12. No 1, 2007 "How does HIV/AIDS cause cardiomyopathy?" p. 27-36; (2007).


    Lewis, William and Currie, Peter, F: "HIV/AIDS and the Cardiovascular System" in Hurst's: The Heart, Chapter 92 pp2118-2131.


    Lewis, William, Reverse Transcriptase Inhibitors in HIV/AIDS Therapy, Humana Press, Inc.; Chapter 9, "Mitochondrial Dysfunction and Nucleoside Reverse Transcriptase Inhibitor Therapy" p. 267-279, (2006)


    Lewis, William: "Toxic Heart Diseases" in Silver's Cardiovascular Pathology 3rd Edition, A gotlieb, F. Schoen, M. Silver, Editors Saunders, Philadelphia.


    Lewis, William: "Clinical Laboratory Analysis of the Genetically Manipulataed Mouse" in "Cardiovascular Physiology in the Genetically Engineered Mouse" 2nd Edition, R. A. Walsh and B. D. Hoit, Editors Kluwer, Norwell, MA. pp 303-317.


    Lewis, William "Pathologic changes in hearts of patients with AIDS in Cardiology in AIDS, S. Lipshultz, Editor; Chapman and Hall, New York


    Lewis, William: "Mitochondrial toxicity of antiviral nucleosides used in AIDS: insights into mitochondrial cardiac and skeletal defects and changes in other tissues rich in mitochondria" in Cardiology in AIDS, S Lipshultz, Editor; Chapman and Hall, New York