Description of Research Expertise:
- Vaccines for prevention of genital herpes
- Immune evasion strategies of Herpes Simplex Virus
Key words: Genital herpes vaccine, HSV immune evasion, glycoprotein gC, glycoprotein gD, glycoprotein E, complement, pathogenesis, antibodies.
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.
The Friedman lab has evaluated vaccine strategies for prevention of genital herpes infection that include approaches to block the immune evasion functions of gC and gE. HSV-2 gC2 and gE2 are expressed at the cell surface and on the virion envelope; therefore, these glycoproteins are potentially accessible to antibodies that are produced by immunization that can bind to the glycoproteins and block their immune evasion functions. Studies in mice and guinea pig models of genital herpes infection indicate that an immunization strategy to block immune evasion is feasible and that adding gC2 and gE2 antigens to a glycoprotein D (gD2)-based vaccine provides potent protection against genital herpes infection as a prophylactic vaccine and that a gC2/gD2/gE2 trivalent subunit antigen vaccine is effective as therapy for prior genital herpes. Recently, the lab has used nucleoside-modified mRNA in lipid nanoparticles to deliver the vaccine antigens to mice and guinea pigs. Immunogenicity and efficacy of the vaccine in pre-clinical testing has been outstanding. The lab is expecting this approach to proceed to human trials within 1-2 years.
Sita Awasthi, Ph.D., Research Associate Professor. Dr. Awasthi is leading the trivalent gC/gD/gE glycoprotein immunization studies in mice and guinea pigs.
Lauren M. Hook, Ph.D., Senior Research Investigator. Dr. Hook is investigating the antibody correlates of protection for a trivalent gC/gD/gE genital herpes vaccine. Her approach is to evaluate the epitope specific antibody responses produced by immunization with the gC, gD and gE immunogens.
Kevin Egan, Ph.D., Post-doctoral Fellow. Dr. Egan is evaluating protection provided by the HSV-2 trivalent gC2/gD2/gE2 vaccine against genital infection by HSV-1 that now comprises almost half of all first time cases of genital herpes.
Philip Latourett, DVMD, Post-doctoral Fellow. Dr. Latourett is a resident in Veterinary Medicine who is evaluating the efficacy of a trivalent HSV vaccine for preventing neonatal herpes in mice and guinea pigs.
Alexis Naughton, Research Specialist. Ms Naughton is evaluating the immune responses to a trivalent gC/gD/gE vaccine in mice and guinea pigs and performing assays to measure HSV DNA copy number in tissues as an approach to assess vaccine efficacy.
John Lubinski, PhD. Dr Lubinski is a research scientist evaluating efficacy of HSV vaccines as therapy for genital herpes in the guinea pig genital herpes model.
Awasthi S, Hook LM, Swaminathan G, Cairns TM, Brooks B, Smith JS, Ditto NT, Gindy ME, Bett AJ, Espeseth AS, Cohen GH, Friedman HM.: Antibody responses to crucial functional epitopes as a novel approach to assess immunogenicity of vaccine adjuvants. Vaccine 37 : 3770-3778,2019.
Lauren M Hook, Sita Awasthi, Jonathan Dubin, Jessica Flechtner, Deborah Long, Harvey M. Friedman: A trivalent gC2/gD2/gE2 vaccine for herpes simplex virus generates antibody responses that block immune evasion domains on gC2 better than natural infection Vaccine 37 : 664-669,2019.
D. Bernstein, R. Cardin, F. Bravo, S. Awasthi, P. Lu, D. Pullum, D. Dixon, A. Iwasaki, H. Friedman: Successful application of prime and pull strategy for a therapeutic HSV vaccine. npj Vaccines : DOI. 10.1038/s41541-019-0129-1,2019.
Hook LM, Cairns TM, Awasthi S, Brooks BD, Ditto NT, Eisenberg RJ, Cohen GH, Friedman HM: Vaccine-induced antibodies to herpes simplex virus glycoprotein D epitopes involved in virus entry and cell-to-cell spread correlate with protection against genital disease in guinea pigs PLOS Pathogens : 2018.
Awasthi S, Hook LM, Shaw CE, Pahar B, Stagray JA, Liu D, Veazey RS, Friedman HM: An HSV-2 trivalent vaccine is immunogenic in rhesus macaques and highly efficacious in guinea pigs PLOS Pathogens ( ): 2017.
S. Awasthi, L. M. Hook, C. E. Shaw, H. M. Friedman: A trivalent subunit antigen glycoprotein vaccine as immunotherapy for genital herpes in the guinea pig genital infection model. Human Vaccines & Immunotherapeutics 13 (12): 2785-2793,2017.
Awasthi, S and Friedman, HM: Molecular association of herpes simplex viurs type 1 glycoprotein E with membrane protein Us9 Archives of Virology 161 (11): 3203-13,2016.
Michael JA Reid, Andrew P Steenhoff, James Thompson, Lesgo Gabaitiri, Mark S Cary, Katherine Steele, Susan Mayisela, Diana Dickinson, Peter Ehrenkranz, Harvey M Friedman, Daren R Linkin: Evaluation of effect of cellular SMS reminders on consistency of antiretroviral therapy pharmacy pick-ups in HIV-infected adults in Botswana: a randomized control trial Health Psychology and Behavioral Medicine 5 (1): 101-109,2017.
Gersh JK, Feldman Z, Greenberger E, Chandra A, Friedman HM, Lere T, Ho-Foster A, Haas MK: Tuberculosis among individuals with community-acquired pneumonia presenting to emergency in Gaborone, Botswana Journal of Public Health in Africa 21 (9): 25-28,2018.
T.E. Major, B. Koyabe, M. Narashmhamurthy, O. Nkomazana, H.M. Friedman: Research mentoring plan involving North-South collaborations. Journal of Global Oncology in press : 2019.
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