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Faculty

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Harvey M. Friedman

Professor of Medicine
Attending Physician, Hospital of the University of Pennsylvania
Director, Botswana UPenn Partnership, University of Pennsylvania
Department: Medicine

Contact information
522E Johnson Pavilion
36th & Hamilton Walk
Philadelphia, PA 19104-6073
Office: 215-573-8432
Fax: 215-349-5111
Graduate Group Affiliations
Education:
B.S.
McGill University, 1965.
M.D.
McGill University, 1969.
Post-Graduate Training
Intern in Medicine, Jewish General Hospital, Montreal, Quebec, Canada, 1969-1970.
First year resident in Medicine, Jewish General Hospital, Montreal, Quebec, 1970-1971.
Virology Fellowship, Wistar Institute, Philadelphia, Pennsylvania, 1971-1973.
Fellow in Infectious Diseases, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, 1973-1975.
Certifications
American Board of Internal Medicine - June 18, 1975, 1975.
Infectious Diseases Boards – October 19, 1976, 1976.
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> Perelman School of Medicine   > Faculty   > Details

Description of Research Expertise

Research Interests
- Immune evasion strategies of Herpes Simplex Virus
- Role of HSV-1 glycoproteins gE and gI in viral transport within neurons.

Key words: HSV immune evasion, glycoprotein gC, glycoprotein gE, complement, pathogenesis.

Description of Research
Dr. Friedman’s laboratory showed that HSV-1 glycoprotein gC binds complement component C3, a critical complement protein central to the classical, lectin and alternative complement pathways. This area of investigation continues to be a focus of the laboratory. The Friedman laboratory showed that gC inhibits C3 activation, rendering the complement system ineffective against HSV. 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. The Friedman laboratory 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 how the virus resists antibody attack. The laboratory constructed an HSV-1 virus mutated in both gC and gE and 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. Recent studies aimed at blocking immune evasion domains on gC and gE demonstrate that antibodies can be produced by immunization that recognize gC and gE domains involved in immune evasion. Therefore, immunization represents a novel approach to treatment and to improving efficacy of subunit HSV vaccines.

A newer area of investigations deals with the role of HSV-1 gE in virus trafficking within the nervous system. Studies in vitro and in a murine eye model indicated that gE null viruses are defective in targeting virions to the axon. Efforts are underway to define gE domains required for axonal localization and mechanisms by which gE mediates these effects.


Lab personnel:
Sita Awasthi, Ph.D., Research Assistant Professor. Dr. Awasthi is preparing mutant HSV-1 viruses for infection in mice to evaluate the receptors used by HSV-1 gD in vivo (in collaboration with the Cohen/Eisenberg lab).

Selected Publications

Awasthi S, Huang J, Shaw C, Friedman HM: Blocking HSV-2 glycoprotein E immune evasion as an approach to enhance efficacy of a trivalent subunit antigen vaccine for genital herpes. Journal of Virology May 2014.

Awasthi S, Belshe RB, Friedman HM: Better neutralization of HSV-1 than HSV-2 by antibody from recipients of GlaxoSmithKline HSV-2 Glycoprotein D2 Subunit Vaccine. Journal of Infectious Diseases April 2014.

Arscott-Mills TA, Ho-Foster A, Lowenstein M, Jibril H, Masunge J, Mweemba P, Nashara P, Makombe R, Chirenda J, Friedman HM, Steenhoff AP, Harari N: Yield of Screening for TB and HIV among Children Failing to Thrive in Botswana. Journal of Tropical Pediatrics 60(1): 27-32, February 2014.

Awasthi S, Balliet JW, Flynn JA, Lubinski JM, Shaw CE, DiStefano DJ, Cai M, Brown M, Smith JF, Kowalski R, Swoyer R, Galli J, Copeland V, Rios S, Davidson RC, Salnikova M, Kingsley S, Bryan J, Casimiro DR, Friedman HM.: Protection provided by a herpes Simplex Virus 2 (HSV-2) Glycoprotein C and D Subunit Antigen Vaccine against Genital HSV-2 Infection in HSV-1-Seropositive Guinea Pigs. Journal of Virology 88(4): 2000-10, February 2014.

Hafkin J, Modongo C, Newcomb C, Lowenthal E, MacGregor R, Steenhoff AP, Friedman HM, Bisson GP: Impact of HIV on Early MDR-TB Treatment Outcomes in Botswana. International J of TB and Lung Disease Int J Tuberc Lung Dis 17(3): 348-53, March 2013.

Ramogola-Masire D, de Klerk R, Monare B, Ratshaa B, Friedman HM, Zetola NM: Cervical Cancer prevention in HIV-infected women using the "see and treat" approach in Botswana. J Acquir Immune Defic Syndr 59(3): 308-13, Mar 2012.

Awasthi S, Zumbrun EE, Si H, Wang F, Shaw CE, Cai M, Lubinski JM, Barrett SM, Balliet JW, Flynn JA, Casimiro CR, Bryan JT, Friedman HM: Live attenuated herpes simplex virus type 2 glycoprotein E deletion mutant as a vaccine candidate defective in neuronal spread. J. Virol. 86: 4586-98, 2012.

Awasthi S, Lubinski JM, Shaw CE, Barrett SM, Cai M, Wang F, Betts M, Kingsley S, DiStefano DJ, Balliet JW, Flynn JA, Casimiro DR, Bryan JT, and Friedman HM: Immunization with a Vaccine Combining Herpes Simplex Virus 2 (HSV-2) Glycoprotein C (gC) and gD Subunits Improves the Protection of Dorsal Root Ganglia in Mice and Reduces the Frequency of Recurrent Vaginal Shedding of HSV-2 DNA in Guinea Pigs Compared to Immunization with gD Alone. Journal of Virology 85(20): 10472-10486, October 2011.

Merlin JS, Morrison G, Gluckman S, Lipschik G, Linkin DR, Lyon S, O'Grady EO, Calvert H, Friedman HM.: Blood and body fluid exposures among US medical students in Botswana. J. Gen Intern Med 26(5): 561-564, May 2011.

Lubinski JM, Lazear HM, Awasthi S, Wang F, Friedman HM.: Herpes simplex virus type 1 IgG Fc receptor blocks antibody-mediated complement activation and antibody-dependent cellular cytotoxicity in vivo. J. Virol 85: 3239-3249, 2011.

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Last updated: 07/10/2014
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