Photo of David M. Knipe,  PhD

David M. Knipe, PhD

Harvard Medical School

Harvard Medical School
Phone: (617) 432-1934
Fax: (617) 432-0223


david_knipe@hms.harvard.edu

David M. Knipe, PhD

Harvard Medical School

EDUCATIONAL TITLES

  • Higgins Professor of Microbio & Molec Genetics, Microbiology and Immunobiology, Harvard Medical School

DF/HCC PROGRAM AFFILIATION

Research Abstract

Our laboratory studies the mechanisms of herpes simplex virus productive infection of epithelial cells and latent infection of neuronal cells and the host immune response to HSV infection. Studies of productive infection involve the mechanisms of regulation of viral gene expression and intranuclear localization of viral regulatory and DNA replication proteins. Our work on latent infection has identified novel gene regulatory pathways in neurons that lead to nonpermissive infection. Our studies of the host immune responses to HSV have led to the development of genetically engineered replication-defective mutant HSV-2 strains as candidate vaccines for genital herpes and as vectors for AIDS vaccines. We are also using HSV vectors to express prostate cancer antigens as potential cancer vaccines, and we are participating in the study and design of HSV strains that specifically kill tumor cells.

Publications

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  • Orzalli MH, Broekema NM, Diner BA, Hancks DC, Elde NC, Cristea IM, Knipe DM. cGAS-mediated stabilization of IFI16 promotes innate signaling during herpes simplex virus infection. Proc Natl Acad Sci U S A 2015; 112:E1773-81. PubMed
  • Hendricks GL, Velazquez L, Pham S, Qaisar N, Delaney JC, Viswanathan K, Albers L, Comolli JC, Shriver Z, Knipe DM, Kurt-Jones EA, Fygenson DK, Trevejo JM, Wang JP, Finberg RW. Heparin octasaccharide decoy liposomes inhibit replication of multiple viruses. Antiviral Res 2015; 116:34-44. PubMed
  • Oh HS, Knipe DM. Proteomic analysis of the herpes simplex Virus 1 virion protein 16 transactivator protein in infected cells. Proteomics 2015. PubMed
  • Knipe DM. Nuclear sensing of viral DNA, epigenetic regulation of herpes simplex virus infection, and innate immunity. Virology 2015. PubMed
  • Deng Z, Kim ET, Vladimirova O, Dheekollu J, Wang Z, Newhart A, Liu D, Myers JL, Hensley SE, Moffat J, Janicki SM, Fraser NW, Knipe DM, Weitzman MD, Lieberman PM. HSV-1 remodels host telomeres to facilitate viral replication. Cell Rep 2014; 9:2263-78. PubMed
  • Knipe DM, Corey L, Cohen JI, Deal CD. Summary and recommendations from a National Institute of Allergy and Infectious Diseases (NIAID) workshop on "Next Generation Herpes Simplex Virus Vaccines". Vaccine 2014; 32:1561-2. PubMed
  • Bonham KS, Orzalli MH, Hayashi K, Wolf AI, Glanemann C, Weninger W, Iwasaki A, Knipe DM, Kagan JC. A promiscuous lipid-binding protein diversifies the subcellular sites of toll-like receptor signal transduction. Cell 2014; 156:705-16. PubMed
  • Colgrove R, Diaz F, Newman R, Saif S, Shea T, Young S, Henn M, Knipe DM. Genomic sequences of a low passage herpes simplex virus 2 clinical isolate and its plaque-purified derivative strain. Virology 2014; 450-451:140-5. PubMed
  • Oh HS, Bryant KF, Nieland TJ, Mazumder A, Bagul M, Bathe M, Root DE, Knipe DM. A targeted RNA interference screen reveals novel epigenetic factors that regulate herpesviral gene expression. MBio 2014; 5:e01086-13. PubMed
  • Orzalli MH, Conwell SE, Berrios C, DeCaprio JA, Knipe DM. Nuclear interferon-inducible protein 16 promotes silencing of herpesviral and transfected DNA. Proc Natl Acad Sci U S A 2013; 110:E4492-501. PubMed
  • Sen J, Liu X, Roller R, Knipe DM. Herpes simplex virus US3 tegument protein inhibits Toll-like receptor 2 signaling at or before TRAF6 ubiquitination. Virology 2013; 439:65-73. PubMed
  • Lee MN, Roy M, Ong SE, Mertins P, Villani AC, Li W, Dotiwala F, Sen J, Doench JG, Orzalli MH, Kramnik I, Knipe DM, Lieberman J, Carr SA, Hacohen N. Identification of regulators of the innate immune response to cytosolic DNA and retroviral infection by an integrative approach. Nat Immunol 2013; 14:179-85. PubMed
  • Cliffe AR, Coen DM, Knipe DM. Kinetics of facultative heterochromatin and polycomb group protein association with the herpes simplex viral genome during establishment of latent infection. MBio 2013. PubMed
  • Orzalli MH, Deluca NA, Knipe DM. Nuclear IFI16 induction of IRF-3 signaling during herpesviral infection and degradation of IFI16 by the viral ICP0 protein. Proc Natl Acad Sci U S A 2012; 109:E3008-17. PubMed
  • Bryant KF, Colgrove RC, Knipe DM. Cellular SNF2H Chromatin-Remodeling Factor Promotes Herpes Simplex Virus 1 Immediate-Early Gene Expression and Replication. MBio 2011. PubMed
  • van Lint AL, Murawski MR, Goodbody RE, Severa M, Fitzgerald KA, Finberg RW, Knipe DM, Kurt-Jones EA. Herpes simplex virus immediate-early ICP0 protein inhibits Toll-like receptor 2-dependent inflammatory responses and NF-kappaB signaling. J Virol 2010; 84:10802-11. PubMed
  • Jurak I, Kramer MF, Mellor JC, van Lint AL, Roth FP, Knipe DM, Coen DM. Numerous Conserved and Divergent MicroRNAs Expressed by Herpes Simplex Viruses 1 and 2. J Virol 2010; 84:4659-72. PubMed
  • Reszka N, Zhou C, Song B, Sodroski JG, Knipe DM. Simian TRIM5alpha proteins reduce replication of herpes simplex virus. Virology 2010; 398:243-50. PubMed
  • Hancock MH, Cliffe AR, Knipe DM, Smiley JR. Herpes simplex virus VP16, but not ICP0, is required to reduce histone occupancy and enhance histone acetylation on viral genomes in U2OS osteosarcoma cells. J Virol 2010; 84:1366-75. PubMed
  • Johnson KE, Knipe DM. Herpes simplex virus-1 infection causes the secretion of a type I interferon-antagonizing protein and inhibits signaling at or before Jak-1 activation. Virology 2009; 396:21-9. PubMed
  • Hoshino Y, Pesnicak L, Dowdell KC, Burbelo PD, Knipe DM, Straus SE, Cohen JI. Protection from herpes simplex virus (HSV)-2 infection with replication-defective HSV-2 or glycoprotein D2 vaccines in HSV-1-seropositive and HSV-1-seronegative guinea pigs. J Infect Dis 2009; 200:1088-95. PubMed
  • Cliffe AR, Garber DA, Knipe DM. Transcription of the herpes simplex virus latency-associated transcript promotes the formation of facultative heterochromatin on lytic promoters. J Virol 2009; 83:8182-90. PubMed
  • Liu X,Broberg E,Watanabe D,Dudek T,Deluca N,Knipe DM. Genetic engineering of a modified herpes simplex virus 1 vaccine vector. Vaccine 2009; 27:2760-7. PubMed
  • Taylor TJ,Knipe DM. The use of green fluorescent fusion proteins to monitor herpes simplex virus replication. Methods Mol Biol 2009; 515:239-48. PubMed
  • Hamirally S,Kamil JP,Ndassa-Colday YM,Lin AJ,Jahng WJ,Baek MC,Noton S,Silva LA,Simpson-Holley M,Knipe DM,Golan DE,Marto JA,Coen DM. Viral mimicry of Cdc2/cyclin-dependent kinase 1 mediates disruption of nuclear lamina during human cytomegalovirus nuclear egress. PLoS Pathog 2009; 5:e1000275. PubMed
  • Brockman MA,Knipe DM. Herpes simplex virus as a tool to define the role of complement in the immune response to peripheral infection. Vaccine 2009; 26 Suppl 8:I94-9. PubMed
  • Cliffe AR,Knipe DM. Herpes simplex virus ICP0 promotes both histone removal and acetylation on viral DNA during lytic infection. J Virol 2008; 82:12030-8. PubMed
  • Liu X,Fitzgerald K,Kurt-Jones E,Finberg R,Knipe DM. Herpesvirus tegument protein activates NF-kappaB signaling through the TRAF6 adaptor protein. Proc Natl Acad Sci U S A 2008; 105:11335-9. PubMed
  • Hoshino Y,Pesnicak L,Dowdell KC,Lacayo J,Dudek T,Knipe DM,Straus SE,Cohen JI. Comparison of immunogenicity and protective efficacy of genital herpes vaccine candidates herpes simplex virus 2 dl5-29 and dl5-29-41L in mice and guinea pigs. Vaccine 2008; 26:4034-40. PubMed
  • Silva L,Cliffe A,Chang L,Knipe DM. Role for A-type lamins in herpesviral DNA targeting and heterochromatin modulation. PLoS Pathog 2008; 4:e1000071. PubMed
  • Dodson AW, Taylor TJ, Knipe DM, Coen DM. Inhibitors of the sodium potassium ATPase that impair herpes simplex virus replication identified via a chemical screening approach. Virology 2007; 366:340-8. PubMed
  • Petit CM, Chouljenko VN, Iyer A, Colgrove R, Farzan M, Knipe DM, Kousoulas KG. Palmitoylation of the cysteine-rich endodomain of the SARS-coronavirus spike glycoprotein is important for spike-mediated cell fusion. Virology 2006; 360:264-74. PubMed
  • Melroe GT, Silva L, Schaffer PA, Knipe DM. Recruitment of activated IRF-3 and CBP/p300 to herpes simplex virus ICP0 nuclear foci: Potential role in blocking IFN-beta induction. Virology 2006; 360:305-21. PubMed
  • Kaur A, Sanford HB, Garry D, Lang S, Klumpp SA, Watanabe D, Bronson RT, Lifson JD, Rosati M, Pavlakis GN, Felber BK, Knipe DM, Desrosiers RC. Ability of herpes simplex virus vectors to boost immune responses to DNA vectors and to protect against challenge by simian immunodeficiency virus. Virology 2006; 357:199-214. PubMed
  • Watanabe D, Brockman MA, Ndung'u T, Mathews L, Lucas WT, Murphy CG, Felber BK, Pavlakis GN, Deluca NA, Knipe DM. Properties of a herpes simplex virus multiple immediate-early gene-deleted recombinant as a vaccine vector. Virology 2006; 357:186-98. PubMed
  • Brockman MA, Verschoor A, Zhu J, Carroll MC, Knipe DM. Optimal long-term humoral responses to replication-defective herpes simplex virus require CD21/CD35 complement receptor expression on stromal cells. J Virol 2006; 80:7111-7. PubMed
  • Palliser D, Chowdhury D, Wang QY, Lee SJ, Bronson RT, Knipe DM, Lieberman J. An siRNA-based microbicide protects mice from lethal herpes simplex virus 2 infection. Nature 2005; 439:89-94. PubMed
  • Wakimoto H, Johnson PR, Knipe DM, Chiocca EA. Effects of innate immunity on herpes simplex virus and its ability to kill tumor cells. Gene Ther 2003; 10:983-90. PubMed
  • de Bruyn Kops A, Uprichard SL, Chen M, Knipe DM. Comparison of the intranuclear distributions of herpes simplex virus proteins involved in various viral functions. Virology 1999; 252:162-78. PubMed
  • Hann LE, Cook WJ, Uprichard SL, Knipe DM, Coen DM. The role of herpes simplex virus ICP27 in the regulation of UL24 gene expression by differential polyadenylation. J Virol 1998; 72:7709-14. PubMed
  • Morrison LA, Da Costa XJ, Knipe DM. Influence of mucosal and parenteral immunization with a replication-defective mutant of HSV-2 on immune responses and protection from genital challenge. Virology 1998; 243:178-87. PubMed
  • Kramer MF, Chen SH, Knipe DM, Coen DM. Accumulation of viral transcripts and DNA during establishment of latency by herpes simplex virus. J Virol 1998; 72:1177-85. PubMed
  • Morrison LA, Knipe DM. Contributions of antibody and T cell subsets to protection elicited by immunization with a replication-defective mutant of herpes simplex virus type 1. Virology 1998; 239:315-26. PubMed
  • Garber DA, Schaffer PA, Knipe DM. A LAT-associated function reduces productive-cycle gene expression during acute infection of murine sensory neurons with herpes simplex virus type 1. J Virol 1997; 71:5885-93. PubMed
  • Da Costa XJ, Bourne N, Stanberry LR, Knipe DM. Construction and characterization of a replication-defective herpes simplex virus 2 ICP8 mutant strain and its use in immunization studies in a guinea pig model of genital disease. Virology 1997; 232:1-12. PubMed
  • Brehm MA, Bonneau RH, Knipe DM, Tevethia SS. Immunization with a replication-deficient mutant of herpes simplex virus type 1 (HSV-1) induces a CD8+ cytotoxic T-lymphocyte response and confers a level of protection comparable to that of wild-type HSV-1. J Virol 1997; 71:3534-44. PubMed
  • Uprichard SL, Knipe DM. Assembly of herpes simplex virus replication proteins at two distinct intranuclear sites. Virology 1997; 229:113-25. PubMed
  • Chen YM, Knipe DM. A dominant mutant form of the herpes simplex virus ICP8 protein decreases viral late gene transcription. Virology 1996; 221:281-90. PubMed
  • Kanangat S, Babu JS, Knipe DM, Rouse BT. HSV-1-mediated modulation of cytokine gene expression in a permissive cell line: selective upregulation of IL-6 gene expression. Virology 1996; 219:295-300. PubMed
  • Liptak LM, Uprichard SL, Knipe DM. Functional order of assembly of herpes simplex virus DNA replication proteins into prereplicative site structures. J Virol 1996; 70:1759-67. PubMed
  • Uprichard SL, Knipe DM. Herpes simplex ICP27 mutant viruses exhibit reduced expression of specific DNA replication genes. J Virol 1996; 70:1969-80. PubMed
  • Davar G, Kramer MF, Garber D, Roca AL, Andersen JK, Bebrin W, Coen DM, Kosz-Vnenchak M, Knipe DM, Breakefield XO. Comparative efficacy of expression of genes delivered to mouse sensory neurons with herpes virus vectors. J Comp Neurol 1994; 339:3-11. PubMed
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