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Member Information
Harvey Friedman, MD
Professor, Department of Medicine
Division Chief, Infectious Diseases
Office Phone: 215-662-3557
Office Fax: 215-349-5111
Email: hfriedma@mail.med.upenn.edu
Website(s): www.harveymfriedman.com
Education: MD 1969, McGill University
Keywords: Herpes simplex virus, immune evasion, pathogenesis, HIV, Africa
Research and/or Clinical Interests:
Defining immune evasion strategies of herpes simplex virus. Epidemiology of the HIV epidemic in Botswana, Africa.
Summary:
The Friedman laboratory showed that HSV-1 glycoprotein gC binds complement component C3, a critical complement protein central to the classical, lectin and alternative complement pathways. We showed that gC inhibits C3 activation, rendering the complement system ineffective against HSV. The domains on gC involved in C3 binding were defined and it was shown that HSV mutant virus lacking the C3 binding domain and cells infected by these mutant viruses are highly susceptible to complement-mediated neutralization or lysis. In vivo studies in guinea pigs and mice demonstrated that gC mutant viruses are 50- to 100-fold less virulent than wild-type virus. Proof that complement accounts for the decreased virulence came from studies in C3-deficient animals in which virulence of gC mutant viruses returned to wild-type levels. These studies demonstrate an important role for gC in immune evasion.
The Friedman laboratory also demonstrated that HSV-1 is able to evade antibody attack. HSV-1 glycoproteins gE and gI form a complex that binds the Fc domain of IgG. We showed that when the Fab domain of an antibody molecule binds to an HSV antigen, the Fc end of the same antibody molecule binds to gE-gI, blocking activities mediated by the Fc domain, such as complement activation and antibody-dependent cellular cytotoxicity. These activities of gE-gI reduce the effectiveness of antibodies, and help to explain virus resistance to antibody attack. Using an HSV-1 virus mutated in both gC and gE, we showed that the two immune evasion glycoproteins function in synergy to protect the virus against antibody and complement attack. The gC or gE mutant viruses are each approximately 100-fold more susceptible to antibody and complement neutralization than wild-type virus; however, the gC-gE double mutant virus is approximately 10,000-fold more susceptible. In a murine model, virulence of the gC-gE double mutant virus is reduced compared with gC or gE single mutant viruses and is 1,000- to 10,000-fold reduced compared with wild-type virus. These studies establish an important role for gC- and gE-mediated immune evasion in HSV-1 pathogenesis. Current studies are aimed at blocking immune evasion domains on gC and gE as a novel approach to treatment and to improving efficacy of subunit HSV vaccines.
Recently, we have initiated clinical research protocols in Botswana , Africa aimed at examining effectiveness of the Botswana National Antiretroviral Therapy program in treating HIV infected subjects. Those interested in learning more about these clinical research trials should contact Harvey Friedman (hfriedma@mail.med.upenn.edu) of Gregory Bission (bisson@mail.med.upenn.edu).
Representative Publications:
Friedman HM, Wang L, Fishman NO, Lambris JD, Eisenberg RJ, Cohen GH, Lubinski J. Immune evasion properties of herpes simplex virus type 1 glycoprotein gC. J Virol 70:4253-4260,1996.
Rux AH, Moore WT, Lambris JD, Abrams WR, Peng C, Friedman HM, Cohen GH, Eisenberg RJ. Disulfide bond structure determination and biochemical analysis of glycoprotein C from herpes simplex virus. J. Virol.70:5455-5465,1996.
Basu S, Dubin G, Nagashunmugam T, Basu M, Goldstein LT, Wang L, Weeks B, Friedman HM. Mapping regions of herpes simplex virus type 1 glycoprotein I required for formation of the viral Fc receptor for monomeric IgG. J. Immunol. 158:209-215,1997.
Kostavasili J, Sahu A, Friedman HM, Eisenberg RJ, Cohen GH, Lambris JD. Mechanism of complement inactivation by glycoprotein C of herpes simplex virus. J Immunol 158:1763-1771, 1997.
Nagashunmugam T, Lubinski J, Wang L, Goldstein LT, Weeks B, Sundaresan P, Kang E, Dubin G, Friedman, HM. In vivo immune evasion mediated by herpes simplex virus type 1 IgG Fc receptor. J Virol 72:5351-5359, 1998.
Lubinski J, Wang L, Soulik A, Burger R, Wetsel RA, Colten H, Cohen GH, Eisenberg RJ, Lambris JD, Friedman HM. Herpes simplex virus type 1 glycoprotein gC mediates immune evasion in vivo. J Virol 72:8257-8263, 1998.
Lubinski J, Wang L, Mastellos D, Sahu A, Lambris JD, Friedman HM. In vivo role of complement interacting domains of herpes simplex virus type 1 glycoprotein gC. J. Exp Med 90:1637-1646, 1999.
Saldanha CE, Lubinski J, Martin C, Nagashunmugam T, Wang L, Van der Keyl H, Tal- Singer R, Friedman HM. Herpes simplex virus type 1 glycoprotein gE domains involved in virus spread and disease. J Virol 74:6712-6719, 2000.
Friedman HM, Wang, L, Pangburn MK, Lambris JD, Lubinski J. Novel mechanism of antibody-independent complement neutralization of herpes simplex virus type 1. J Immunol 165:4528-4536, 2000.
Rux AH, Lou H, Lambris JD, Friedman HM, Eisenberg RJ, Cohen GH. Kinetic analysis of glycoprotein C of herpes simplex virus types 1 and 2 binding to heparin, heparan sulfate and complement component C3b. Virology 294:324-332, 2002.
Lubinski JM, Jiang M, Hook L, Chang Y, Sarver C, Mastellos D, Lambris JD, Cohen GH, Eisenberg RJ, Friedman HM. 2002. Herpes Simplex Virus Type 1 Evades the Effects of Antibody and Complement in Vivo. J Virol 76:9232-9241.
Nagashunmugam T, Malamud D, Davis C, Abrams WR, Friedman HM. 1998. Human submandibular saliva inhibits HIV-1 infection by displacing envelope glycprotein gp120 from the virus. J Infect Dis 178:1635-1641.
