David M. Knipe

Last updated
David M. Knipe
Born
David Mahan Knipe

Lancaster, Ohio
CitizenshipUSA
Alma mater Case Western Reserve University B.A.
Massachusetts Institute of Technology Ph.D.
University of Chicago Post-doctoral training
Known for Herpes simplex virus research
Fields Virology
Scientific career
Fields Virology
Microbiology
Institutions Harvard Medical School

David Mahan Knipe is the Higgins Professor of Microbiology and Molecular Genetics in the Department of Microbiology at the Harvard Medical School in Boston, Massachusetts [1] and co-chief editor of the reference book Fields Virology. [2] He returned to the Chair of the Program in Virology at Harvard Medical School in 2019, having previously held the position from 2004 through 2016 and served as interim Co-Chair of the Microbiology and Immunobiology Department from 2016 through 2018.

Contents

Education

Knipe was educated at Case Western Reserve University, receiving a B.A. summa cum laude in biology in 1972. At CWRU, he conducted research with Dr. Robert D. Goldman and showed that microfilaments in mammalian cells were actin filaments through the binding of purified heavy meromyosin to decorate the microfilaments in permeabilized cells. [3] He continued his studies in cell biology at the Massachusetts Institute of Technology, earning his Ph.D. in 1976; his thesis research focused on vesicular stomatitis virus (VSV) under the supervision of Dr. David Baltimore and Dr. Harvey Lodish. Knipe first separated and translated the VSV mRNAs in vitro to identify their coding potential. He then showed that the VSV glycoprotein (G) and membrane (M) proteins are assembled into virions by two separate pathways. The pathway for G protein helped defined the secretory pathway for membrane glycoprotein assembly and the pathway for the M protein defined a cytosolic pathway for membrane protein assembly. [4] [5] [6] [7]

Following the completion of his graduate studies, he trained as post-doctoral fellow on molecular genetics of herpes simplex virus (HSV) at the University of Chicago with Dr. Bernard Roizman. Knipe developed a cotransfection method for marker rescue mapping of mutations and introduction of new sequences into the HSV genome and showed that the ICP4 gene mapped in the repeated sequences of the short component of the viral genome. [8] This methodology was used to map viral glycoproteins, plaque morphology, and drug resistance markers, and to construct a genital herpes vaccine candidate. [9]

Research

In 1979, Knipe joined the faculty at Harvard Medical School as an assistant professor of Microbiology and Molecular Genetics and established his own lab to study HSV. He showed that HSV replicates its DNA in defined compartments in the infected cell nucleus. [10] [11] They further showed that the viral genome associated with the nuclear lamina for immediate-early transcription. This work revealed that intranuclear proteins are localized to specific sites to carry out their functions, much as cytoplasmic proteins were known to localize to specific sites. This led to new areas of study of intranuclear compartmentalization of DNA virus replication. Knipe's research has shown that host cell DNA repair and recombination proteins are localized to the viral replication compartments and that some of these inhibit viral replication while some are essential for viral replication. [12] He discovered the molecular basis of herpes simplex virus lytic and latent infection through the definition of epigenetic regulatory mechanisms in which: viral proteins promote euchromatin modifications on viral chromatin and transcription of lytic genes in epithelial cells; and the viral latency-associated transcript promotes heterochromatin modifications on viral chromatin and silencing of lytic genes in neurons. [13] [14] [15] He defined the structure of viral chromatin during latent infection of neurons and the mechanisms by which viral DNA is kept silenced during latent infection. [16] [17] [18] He has also defined the cellular proteins that recognize herpesviral DNA in the nucleus and initiate innate signaling and restrict viral gene expression and identified viral proteins that block host innate responses. [19] [20] [21] [22] His work has shown that replication-defective viruses can serve as a genital herpes vaccine and as a vaccine vector—one of these genital herpes vaccines, HSV-529, is the leading candidate in phase I clinical trials. [9] [23] [24]

Awards and honors

Knipe has received several honors and awards including:

Personal life

Knipe is married to Suzanne Knipe; they have two daughters and four grandchildren.

Related Research Articles

<span class="mw-page-title-main">Epstein–Barr virus</span> Virus of the herpes family

The Epstein–Barr virus (EBV), formally called Human gammaherpesvirus 4, is one of the nine known human herpesvirus types in the herpes family, and is one of the most common viruses in humans. EBV is a double-stranded DNA virus. Epstein–Barr virus (EBV) is the first identified oncogenic virus, which establishes permanent infection in humans. EBV causes infectious mononucleosis and is also tightly linked to many malignant diseases. Various vaccine formulations underwent testing in different animals or in humans. However, none of them were able to prevent EBV infection and no vaccine has been approved to date.

<span class="mw-page-title-main">Kaposi's sarcoma-associated herpesvirus</span> Species of virus

Kaposi's sarcoma-associated herpesvirus (KSHV) is the ninth known human herpesvirus; its formal name according to the International Committee on Taxonomy of Viruses (ICTV) is Human gammaherpesvirus 8, or HHV-8 in short. Like other herpesviruses, its informal names are used interchangeably with its formal ICTV name. This virus causes Kaposi's sarcoma, a cancer commonly occurring in AIDS patients, as well as primary effusion lymphoma, HHV-8-associated multicentric Castleman's disease and KSHV inflammatory cytokine syndrome. It is one of seven currently known human cancer viruses, or oncoviruses. Even after many years since the discovery of KSHV/HHV8, there is no known cure for KSHV associated tumorigenesis.

Viral pathogenesis is the study of the process and mechanisms by which viruses cause diseases in their target hosts, often at the cellular or molecular level. It is a specialized field of study in virology.

<span class="mw-page-title-main">Lysogenic cycle</span> Process of virus reproduction

Lysogeny, or the lysogenic cycle, is one of two cycles of viral reproduction. Lysogeny is characterized by integration of the bacteriophage nucleic acid into the host bacterium's genome or formation of a circular replicon in the bacterial cytoplasm. In this condition the bacterium continues to live and reproduce normally, while the bacteriophage lies in a dormant state in the host cell. The genetic material of the bacteriophage, called a prophage, can be transmitted to daughter cells at each subsequent cell division, and later events can release it, causing proliferation of new phages via the lytic cycle.

Virus latency is the ability of a pathogenic virus to lie dormant within a cell, denoted as the lysogenic part of the viral life cycle. A latent viral infection is a type of persistent viral infection which is distinguished from a chronic viral infection. Latency is the phase in certain viruses' life cycles in which, after initial infection, proliferation of virus particles ceases. However, the viral genome is not eradicated. The virus can reactivate and begin producing large amounts of viral progeny without the host becoming reinfected by new outside virus, and stays within the host indefinitely.

HHV Latency Associated Transcript is a length of RNA which accumulates in cells hosting long-term, or latent, Human Herpes Virus (HHV) infections. The LAT RNA is produced by genetic transcription from a certain region of the viral DNA. LAT regulates the viral genome and interferes with the normal activities of the infected host cell.

<i>Herpesviridae</i> Family of DNA viruses

Herpesviridae is a large family of DNA viruses that cause infections and certain diseases in animals, including humans. The members of this family are also known as herpesviruses. The family name is derived from the Greek word ἕρπειν, referring to spreading cutaneous lesions, usually involving blisters, seen in flares of herpes simplex 1, herpes simplex 2 and herpes zoster (shingles). In 1971, the International Committee on the Taxonomy of Viruses (ICTV) established Herpesvirus as a genus with 23 viruses among four groups. As of 2020, 115 species are recognized, all but one of which are in one of the three subfamilies. Herpesviruses can cause both latent and lytic infections.

<span class="mw-page-title-main">HHV Infected Cell Polypeptide 0</span> Protein

Human Herpes Virus (HHV) Infected Cell Polypeptide 0 (ICP0) is a protein, encoded by the DNA of herpes viruses. It is produced by herpes viruses during the earliest stage of infection, when the virus has recently entered the host cell; this stage is known as the immediate-early or α ("alpha") phase of viral gene expression. During these early stages of infection, ICP0 protein is synthesized and transported to the nucleus of the infected host cell. Here, ICP0 promotes transcription from viral genes, disrupts structures in the nucleus known as nuclear dots or promyelocytic leukemia (PML) nuclear bodies, and alters the expression of host and viral genes in combination with a neuron specific protein. At later stages of cellular infection, ICP0 relocates to the cell cytoplasm to be incorporated into new virion particles.

<span class="mw-page-title-main">Herpes simplex virus</span> Species of virus

Herpes simplex virus1 and 2, also known by their taxonomic names Human alphaherpesvirus 1 and Human alphaherpesvirus 2, are two members of the human Herpesviridae family, a set of viruses that produce viral infections in the majority of humans. Both HSV-1 and HSV-2 are very common and contagious. They can be spread when an infected person begins shedding the virus.

<i>Gammaherpesvirinae</i> Subfamily of viruses

Gammaherpesvirinae is a subfamily of viruses in the order Herpesvirales and in the family Herpesviridae. Viruses in Gammaherpesvirinae are distinguished by reproducing at a more variable rate than other subfamilies of Herpesviridae. Mammals serve as natural hosts. There are 43 species in this subfamily, divided among 7 genera with three species unassigned to a genus. Diseases associated with this subfamily include: HHV-4: infectious mononucleosis. HHV-8: Kaposi's sarcoma.

<span class="mw-page-title-main">Viral entry</span> Earliest stage of infection in the viral life cycle

Viral entry is the earliest stage of infection in the viral life cycle, as the virus comes into contact with the host cell and introduces viral material into the cell. The major steps involved in viral entry are shown below. Despite the variation among viruses, there are several shared generalities concerning viral entry.

A helper dependent virus, also termed a gutless virus, is a synthetic viral vector dependent on the assistance of a helper virus in order to replicate, and can be used for purposes such as gene therapy. Naturally-occurring satellite viruses are also helper virus dependent, and can sometimes be modified to become viral vectors.

<i>Human betaherpesvirus 5</i> Species of virus

Human betaherpesvirus 5, also called human cytomegalovirus (HCMV,HHV-5), is a species of virus in the genus Cytomegalovirus, which in turn is a member of the viral family known as Herpesviridae or herpesviruses. It is also commonly called CMV. Within Herpesviridae, HCMV belongs to the Betaherpesvirinae subfamily, which also includes cytomegaloviruses from other mammals. CMV is a double-stranded DNA virus.

Anthony (Tony) Charles Minson, PhD, FMedSci is a British virologist known for his work on the biology of herpesviruses, and a university administrator. He was the Senior Pro-Vice-Chancellor of the University of Cambridge from 2003 to 2009. He is an emeritus professor of virology at the university's Department of Pathology and an emeritus fellow of Wolfson College.

Herpes simplex research includes all medical research that attempts to prevent, treat, or cure herpes, as well as fundamental research about the nature of herpes. Examples of particular herpes research include drug development, vaccines and genome editing. HSV-1 and HSV-2 are commonly thought of as oral and genital herpes respectively, but other members in the herpes family include chickenpox (varicella/zoster), cytomegalovirus, and Epstein-Barr virus. There are many more virus members that infect animals other than humans, some of which cause disease in companion animals or have economic impacts in the agriculture industry.

ICP8, the herpes simplex virus type-1 single-strand DNA-binding protein, is one of seven proteins encoded in the viral genome of HSV-1 that is required for HSV-1 DNA replication. It is able to anneal to single-stranded DNA (ssDNA) as well as melt small fragments of double-stranded DNA (dsDNA); its role is to destabilize duplex DNA during initiation of replication. It differs from helicases because it is ATP- and Mg2+-independent. In cells infected with HSV-1, the DNA in those cells become colocalized with ICP8.

<span class="mw-page-title-main">Epigenetics of human herpesvirus latency</span>

Human herpes viruses, also known as HHVs, are part of a family of DNA viruses that cause several diseases in humans. One of the most notable functions of this virus family is their ability to enter a latent phase and lay dormant within animals for extended periods of time. The mechanism that controls this is very complex because expression of viral proteins during latency is decreased a great deal, meaning that the virus must have transcription of its genes repressed. There are many factors and mechanisms that control this process and epigenetics is one way this is accomplished. Epigenetics refers to persistent changes in expression patterns that are not caused by changes to the DNA sequence. This happens through mechanisms such as methylation and acetylation of histones, DNA methylation, and non-coding RNAs (ncRNA). Altering the acetylation of histones creates changes in expression by changing the binding affinity of histones to DNA, making it harder or easier for transcription machinery to access the DNA. Methyl and acetyl groups can also act as binding sites for transcription factors and enzymes that further modify histones or alter the DNA itself.

HSV epigenetics is the epigenetic modification of herpes simplex virus (HSV) genetic code.

Patricia Gail Spear is an American virologist. She is a professor emeritus of microbiology and immunology at Northwestern University in Evanston, Illinois. She is best known for her pioneering work studying the herpes simplex virus. Spear is a past president of the American Society for Virology and an elected member of the National Academy of Sciences.

Jay Clark Brown is an American molecular biologist, microbiologist, virologist, and academic. He is a Professor Emeritus in the Department of microbiology, immunology, and cancer biology at the University of Virginia School of Medicine.

References

  1. ↑ "Department of Microbiology and Immunobiology | Faculty and Their Research". Archived from the original on December 25, 2014. Retrieved January 15, 2015.
  2. ↑ "Fields Virology". Archived from the original on January 3, 2015. Retrieved January 15, 2015.
  3. ↑ Goldman, R. D.; Knipe, D. M. (1973). "Functions of Cytoplasmic fibers in non-muscle cell motility". Cold Spring Harbor Symposia on Quantitative Biology. 37: 523–534. doi:10.1101/sqb.1973.037.01.063.
  4. ↑ Knipe, D. M.; Lodish, H. F.; Baltimore, D. (1977). "Localization of two cellular forms of the vesicular stomatitis viral glycoprotein". Journal of Virology. 21 (3): 1121–1127. doi:10.1128/JVI.21.3.1121-1127.1977. PMC   515653 . PMID   191639.
  5. ↑ Knipe, D. M.; Baltimore, D.; Lodish, H. F. (1977). "Separate pathways of maturation of the major structural proteins of vesicular stomatitis virus". Journal of Virology. 21 (3): 1128–1139. doi:10.1128/JVI.21.3.1128-1139.1977. PMC   515654 . PMID   191640.
  6. ↑ Knipe, D. M.; Lodish, H. F.; Baltimore, D. (1977). "Analysis of the defects of temperature-sensitive mutants of vesicular stomatitis virus: intracellular degradation of specific viral proteins". Journal of Virology. 21 (3): 1140–1148. doi:10.1128/JVI.21.3.1140-1148.1977. PMC   515655 . PMID   191641.
  7. ↑ Knipe, D. M.; Baltimore, D.; Lodish, H. F. (1977). "Maturation of viral proteins in cells infected with temperature-sensitive mutants of vesicular stomatitis virus". Journal of Virology. 21 (3): 1149–1158. doi:10.1128/JVI.21.3.1149-1158.1977. PMC   515656 . PMID   191642.
  8. ↑ Knipe, D. M.; Ruyechan, W. T.; Roizman, B.; Halliburton, I. W. (1978). "Molecular genetics of herpes simplex virus: Demonstration of regions of obligatory and nonobligatory identity within diploid regions of the genome by sequence replacement and insertion". Proceedings of the National Academy of Sciences. 75 (8): 3896–3900. Bibcode:1978PNAS...75.3896K. doi: 10.1073/pnas.75.8.3896 . ISSN   0027-8424. PMC   392895 . PMID   211508.
  9. 1 2 Da Costa, X. J.; Jones, C. A.; Knipe, D. M. (1999). "Immunization against genital herpes with a vaccine virus that has defects in productive and latent infection". Proceedings of the National Academy of Sciences. 96 (12): 6994–6998. Bibcode:1999PNAS...96.6994D. doi: 10.1073/pnas.96.12.6994 . ISSN   0027-8424. PMC   22033 . PMID   10359827.
  10. ↑ Quinlan, Margaret P.; Chen, Lan Bo; Knipe, David M. (1984). "The intranuclear location of a herpes simplex virus DNA-binding protein is determined by the status of viral DNA replication". Cell. 36 (4): 857–868. doi:10.1016/0092-8674(84)90035-7. ISSN   0092-8674. PMID   6323024. S2CID   46351838.
  11. ↑ Kops, Anne de Bruyn; Knipe, David M. (1988). "Formation of DNA replication structures in herpes virus-infected cells requires a viral DNA binding protein". Cell. 55 (5): 857–868. doi:10.1016/0092-8674(88)90141-9. ISSN   0092-8674. PMID   2847874. S2CID   38761659.
  12. ↑ Taylor, T. J.; Knipe, D. M. (2004). "Proteomics of Herpes Simplex Virus Replication Compartments: Association of Cellular DNA Replication, Repair, Recombination, and Chromatin Remodeling Proteins with ICP8". Journal of Virology. 78 (11): 5856–5866. doi:10.1128/JVI.78.11.5856-5866.2004. ISSN   0022-538X. PMC   415816 . PMID   15140983.
  13. ↑ Wang, Q.-Y.; Zhou, C.; Johnson, K. E.; Colgrove, R. C.; Coen, D. M.; Knipe, D. M. (2005). "Herpesviral latency-associated transcript gene promotes assembly of heterochromatin on viral lytic-gene promoters in latent infection". Proceedings of the National Academy of Sciences. 102 (44): 16055–16059. Bibcode:2005PNAS..10216055W. doi: 10.1073/pnas.0505850102 . ISSN   0027-8424. PMC   1266038 . PMID   16247011.
  14. ↑ Cliffe, A. R.; Knipe, D. M. (2008). "Herpes Simplex Virus ICP0 Promotes both Histone Removal and Acetylation on Viral DNA during Lytic Infection". Journal of Virology. 82 (24): 12030–12038. doi:10.1128/JVI.01575-08. ISSN   0022-538X. PMC   2593313 . PMID   18842720.
  15. ↑ Knipe, David M.; Cliffe, Anna (2008). "Chromatin control of herpes simplex virus lytic and latent infection". Nature Reviews Microbiology. 6 (3): 211–221. doi:10.1038/nrmicro1794. ISSN   1740-1526. PMID   18264117. S2CID   14540640.
  16. ↑ Cliffe, A. R.; Garber, D. A.; Knipe, D. M. (2009). "Transcription of the Herpes Simplex Virus Latency-Associated Transcript Promotes the Formation of Facultative Heterochromatin on Lytic Promoters". Journal of Virology. 83 (16): 8182–8190. doi:10.1128/JVI.00712-09. ISSN   0022-538X. PMC   2715743 . PMID   19515781.
  17. ↑ Cliffe, A. R.; Coen, D. M.; Knipe, D. M. (2013). "Kinetics of Facultative Heterochromatin and Polycomb Group Protein Association with the Herpes Simplex Viral Genome during Establishment of Latent Infection" (PDF). mBio. 4 (1): e00590-12–e00590-12. doi:10.1128/mBio.00590-12. ISSN   2150-7511. PMC   3551550 . PMID   23322639.
  18. ↑ Knipe, David M.; Lieberman, Paul M.; Jung, Jae U.; McBride, Alison A.; Morris, Kevin V.; Ott, Melanie; Margolis, David; Nieto, Amelia; Nevels, Michael; Parks, Robin J.; Kristie, Thomas M. (2013). "Snapshots: Chromatin control of viral infection". Virology. 435 (1): 141–156. doi:10.1016/j.virol.2012.09.023. ISSN   0042-6822. PMC   3531885 . PMID   23217624.
  19. ↑ Orzalli, M. H.; DeLuca, N. A.; Knipe, D. M. (2012). "Nuclear IFI16 induction of IRF-3 signaling during herpesviral infection and degradation of IFI16 by the viral ICP0 protein". Proceedings of the National Academy of Sciences. 109 (44): E3008–E3017. doi: 10.1073/pnas.1211302109 . ISSN   0027-8424. PMC   3497734 . PMID   23027953.
  20. ↑ Orzalli, M. H.; Conwell, S. E.; Berrios, C.; DeCaprio, J. A.; Knipe, D. M. (2013). "Nuclear interferon-inducible protein 16 promotes silencing of herpesviral and transfected DNA". Proceedings of the National Academy of Sciences. 110 (47): E4492–E4501. Bibcode:2013PNAS..110E4492O. doi: 10.1073/pnas.1316194110 . ISSN   0027-8424. PMC   3839728 . PMID   24198334.
  21. ↑ Orzalli, Megan H.; Knipe, David M. (2014). "Cellular Sensing of Viral DNA and Viral Evasion Mechanisms". Annual Review of Microbiology. 68 (1): 477–492. doi:10.1146/annurev-micro-091313-103409. ISSN   0066-4227. PMC   4348004 . PMID   25002095.
  22. ↑ Orzalli, Megan H.; Broekema, Nicole M.; Diner, Benjamin A.; Hancks, Dustin C.; Elde, Nels C.; Cristea, Ileana M.; Knipe, David M. (2015). "cGAS-mediated stabilization of IFI16 promotes innate signaling during herpes simplex virus infection". Proceedings of the National Academy of Sciences. 112 (14): E1773–E1781. Bibcode:2015PNAS..112E1773O. doi: 10.1073/pnas.1424637112 . ISSN   0027-8424. PMC   4394261 . PMID   25831530.
  23. ↑ Dudek, T. E.; Torres-Lopez, E.; Crumpacker, C.; Knipe, D. M. (2011). "Evidence for Differences in Immunologic and Pathogenesis Properties of Herpes Simplex Virus 2 Strains From the United States and South Africa". Journal of Infectious Diseases. 203 (10): 1434–1441. doi:10.1093/infdis/jir047. ISSN   0022-1899. PMC   3080912 . PMID   21498376.
  24. ↑ Knipe, David M.; Corey, Lawrence; Cohen, Jeffrey I.; Deal, Carolyn D. (2014). "Summary and recommendations from a National Institute of Allergy and Infectious Diseases (NIAID) workshop on "Next Generation Herpes Simplex Virus Vaccines"". Vaccine. 32 (14): 1561–1562. doi:10.1016/j.vaccine.2014.01.052. ISSN   0264-410X. PMC   4786164 . PMID   24480025.
  25. ↑ "News from the National Academy of Sciences". April 26, 2021. Retrieved July 4, 2021. Newly elected members and their affiliations at the time of election are: … Knipe, David M.; Higgins Professor of Microbiology and Molecular Genetics, department of microbiology, Harvard Medical School, Boston, entry in member directory: "Member Directory". National Academy of Sciences. Retrieved July 4, 2021.
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