Cellular Homologs of Herpesvirus Genes

Cohen, Jeffrey

Abstract

Herpesviruses have developed strategies to counteract host defenses so as to allow viruses to infect cells and result in a latent or persistent infection. The goal of this project is to identify and determine the function of herpesvirus proteins that interact with host cell proteins to influence the course of infection. These proteins may allow us to identify new molecules that are important in the human immune system.Programmed cell death (apoptosis) is an antiviral defense mechanism used by the host to eliminate virus-infected cells. Some viruses encode proteins that interfere with signaling pathways for apoptosis. We have identified a protein encoded by a DNA virus, that inhibits programmed cell death. This virus, murine herpesvirus 68, shares several properties with the human Epstein-Barr virus. The M11 protein of murine herpesvirus 68 is homologous to a cellular protein, bcl-2, that is also known to inhibit programmed cell death. We have shown that the M11 protein inhibits programmed cell death induced by tumor necrosis factor and by the fas protein. In addition, we have also identified a domain within the viral protein that is required for inhibition of cell death.Interleukin-17 is a cytokine present in the human and mouse genomes that is also encoded by a monkey herpesvirus (herpesvirus saimiri). This virus naturally infects squirrel monkeys, but causes lymphomas in tamarins and can transform human T lymphocytes. We have found that when IL-17 is expressed by a virus, IL-17 enhanced the virulence of the virus and increased the replication of the virus in certain tissues. IL-17 inhibited the activity of natural killer cells, but did not affect the activity of cytotoxic T cells. IL-17 inhibited expression of another cytokine-interferon-alpha. IL-17 also altered the pattern of virus-specific antibody production. Taken together, these results suggest that IL-17 may allow the virus to modulate the immune system so that it can persist in animals despite an immune response.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Allergy and Infectious Diseases (NIAID)
• Type: Intramural Research (Z01)
• Project #: 1Z01AI000710-07
• Application #: 6431640
• Study Section: (LCI)
• Support Year: 7
• Fiscal Year: 2000

Institution

• Name: Niaid Extramural Activities
• Country: United States

Publications

Cohen, Jeffrey I (2005) Licking latency with licorice. J Clin Invest 115:591-3

Prikhod'ko, Elena A; Prikhod'ko, Grigori G; Siegel, Richard M et al. (2004) The NS3 protein of hepatitis C virus induces caspase-8-mediated apoptosis independent of its protease or helicase activities. Virology 329:53-67

Sosnovtsev, Stanislav V; Prikhod'ko, Elena A; Belliot, Gael et al. (2003) Feline calicivirus replication induces apoptosis in cultured cells. Virus Res 94:1-10

Kotelkin, Alexander; Prikhod'ko, Elena A; Cohen, Jeffrey I et al. (2003) Respiratory syncytial virus infection sensitizes cells to apoptosis mediated by tumor necrosis factor-related apoptosis-inducing ligand. J Virol 77:9156-72

Patera, Andriani; Ali, Mir A; Tyring, Stephen et al. (2002) Polymorphisms in the genes for herpesvirus entry. J Infect Dis 186:444-5

Garvey, Tara L; Bertin, John; Siegel, Richard M et al. (2002) Binding of FADD and caspase-8 to molluscum contagiosum virus MC159 v-FLIP is not sufficient for its antiapoptotic function. J Virol 76:697-706

Patera, Andriani C; Pesnicak, Lesley; Bertin, John et al. (2002) Interleukin 17 modulates the immune response to vaccinia virus infection. Virology 299:56-63

Prikhod'ko, Grigori G; Prikhod'ko, Elena A; Pletnev, Alexander G et al. (2002) Langat flavivirus protease NS3 binds caspase-8 and induces apoptosis. J Virol 76:5701-10

Garvey, Tara; Bertin, John; Siegel, Richard et al. (2002) The death effector domains (DEDs) of the molluscum contagiosum virus MC159 v-FLIP protein are not functionally interchangeable with each other or with the DEDs of caspase-8. Virology 300:217-25

Prikhod'ko, G G; Prikhod'ko, E A; Cohen, J I et al. (2001) Infection with Langat Flavivirus or expression of the envelope protein induces apoptotic cell death. Virology 286:328-35