Harvey M. Friedman, M.D.
Professor, Dept of Medicine
Chief, Infectious Diseases

Microbiology, Virology and Parasitology Program

Address

502 Johnson Pavilion/6073 (office)
508 Johnson Pavilion (lab)
3610 Hamilton Walk
Philadelphia, PA 19104-6073

Office tel.: 215 662-3557
Fax: 215 349-5111
E-mail: hfriedma@mail.med.upenn.edu

Link(s)

Dr. Friedman's webpage

Education

McGill University: BS, 1965.

McGill University: MD, 1969.

Jewish General Hospital, Montreal, Quebec, Canada: Internship & Residency (Internal Medicine), 1969-71.

The Wistar Institute: Fellowship (Virology), 1971-73.

University of Pennsylvania: Fellowship (Infectious Disease), 1973-75.

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.

Search PubMed for articles

Description of Research

Dr. Friedman’s laboratory was among the first to describe specific herpes simplex virus (HSV) molecules that participate in immune evasion. The laboratory showed in 1984 that HSV-1 glycoprotein gC binds complement component C3b, a critical complement protein central to the classical, lectin and alternative complement pathways. This area of investigation continues as a focus of the laboratory. His laboratory showed that gC inhibits C3 activation, rendering the complement system ineffective against HSV. In collaboration with Drs. Cohen and Eisenberg, the domains on gC involved in C3b binding were defined. The Friedman lab showed that HSV mutant viruses lacking the C3b binding domain are highly susceptible to complement-mediated neutralization, while cells infected by these mutant viruses are more susceptible to complement mediated cell lysis. In vivo studies in guinea pigs and mice demonstrated that gC mutant viruses are 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.

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. His 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 the resistance of the virus to antibody attack. An HSV-1 virus mutated in both gC and gE demonstrated that the two immune evasion glycoproteins function in synergy to protect the virus against antibody and complement attack. In a murine model, virulence of the gC-gE double mutant virus was reduced by 3-4 orders of magnitude compared with wild-type virus. These studies established an important role for gC- and gE-mediated immune evasion in HSV-1 pathogenesis.

A new area of investigation in the laboratory examines virus spread in neurons, which is another function mediated by HSV-1 gE. Using a mouse retina infection model and in vitro infection of rat superior cervical ganglion neurons, the laboratory showed that gE is required for anterograde transport of viral membrane, capsid and tegument proteins from the neuron cell body into axons. These studies identify a critical role for HSV-1 gE for virus trafficking in neurons, which is an essential feature of HSV-1 pathogenesis. Based on the spread defects of the HSV-1 gE mutant virus, the Friedman laboratory is working on a live virus HSV vaccine that has the properties of being replication competent but defective for spread in neurons.

Recent Publications

Xiaoqing L, Lubinski JM, Friedman HM. Immunization Strategies to Block the Herpes Simplex Virus Type 1 IgG Fc Receptor. J. Virol 78:2562-2571, 2004.

Bhuyan P, Kariko K, Capodici J, Lubinski J, Hook L, Friedman H, Weissman D. siRNA-mediated inhibition of HSV-1 gene expression and function during infection of human keratinocytes. J Virol 78:10276-10281, 2004.

Chang YJ, Jiang M, Lubinski JM, King RD, Friedman HM. Implications for herpes simplex virus vaccine strategies based on antibodies produce to herpes simplex virus type 1 glycoprotein gC immune evasion domains. Vaccine 23:4658-4665, 2005.

Wang F, Tang W, McGraw HM, Bennett J, Enquist LW, Friedman HM. Herpes simplex virus type 1 glycoprotein E is required for axonal localization of capsid, tegument and membrane glycoproteins. J Virol 79:13362-72, 2005.

Hook LM, Lubinski JM, Jiang M, Pangburn MK, Friedman HM. Herpes simplex virus type 1 and 2 glycoprotein C prevents complement-mediated neutralization induced by natural IgM antibody. J Virol 80:4038-4046, 2006.

Lab

Rotation Projects

Rotation projects will depend on the interest of the student. Examples include:

1. Preparing mutant and restored viruses for in vitro and in vivo experiments. Students will isolate HSV-1 DNA and use PCR amplification to modify regions of immune evasion genes gC and gE that are the focus of investigations in the lab. The altered genes will be co-transfected with viral DNA into cells and the recombinant virus purified and evaluated for immune evasion activities in vitro and in murine models.


2. Evaluating novel approaches to HSV-1 vaccines. Efforts are underway to develop live virus vaccines for HSV-1 and HSV-2. Students will work under the supervision of a senior investigator in the lab to evaluate either the safety or effectiveness of vaccine candidates in small animal models. Possible projects include measuring viral DNA in dorsal root ganglia of mice by quantitative PCR, performing viral titers on mouse tissues, or examining mouse tissues by histopathology and immunohistochemistry.


3. Exploring mechanisms by which HSV-2 gC and gE/gI modify the innate and acquired immune responses to infection. We have explored the role of HSV-1 gC, gE/gI in immune evasion, but know little about the contributions of HSV-2 gC, gE/gI. Our preliminary results suggest some similarities and some differences comparing the two viruses. Students will evaluate complement and antibody evasion strategies mediated by HSV-2 gC, gE/gI using in vitro assays well established in the laboratory.

Lab personnel:

John Lubinski, Ph.D. Dr. Lubinski is the laboratory manager. He has more than 15 years of experience in molecular virology and animal experimentation. His work focuses on animal models of HSV pathogenesis.

Sita Awasthi, Ph.D., Research Assistant Professor. Dr. Awasthi has been working in the Friedman laboratory for over 4 years and is an experienced virologist. Her focus is on developing HSV-1 and HDV-2 subunit vaccines.

Elizabeth Brittle, Ph.D.. Dr. Brittle is a post-doctoral fellow and is working on live virus vaccines for HSV-1 and HSV-2.

Ryan King is a CAMB graduate student working on immune evasion properties of HSV-1 gC.

Helen McGraw is a CAMB graduate student working on the role of HSV-1 gE in retrograde spread of virus in neurons.

Susan Roth is a CAMP graduate student working on the role of HSV-1 gE in neuronal spread.