Description of Research Expertise:
- 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.
In recent years, 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 highly effective as therapy for prior genital herpes.
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).
Lauren M. Hook, Ph.D., Senior Research Investigator. Dr. Hook is investigating whether the addition of subunit antigens derived from HSV immune evasion glycoproteins C and E improves the efficacy of a gD2-containing subunit antigen vaccine. A secondary project involves evaluating whether HSV-encoded microRNAs contribute to the ability of HSV to evade host immune responses.
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.
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.
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.
Shih-Chuan Liao, Jing Peng, Michael G. Mauk, Sita Awasthi, Jinzhao Song, Harvey Friedman, Haim H. Bau, and Changchun Liu: Smart Cup: A Minimally-Instrumented, Smartphone-Based Point-of-Care Molecular Diagnostic Device Sensors and Actuators: B. Chemical 229 : 232-238,2016.
Awasthi S, Mahairas GS, Shaw CE, Huang M-L, Koelle DM, Posavad C, Corey L, Friedman HM.: A dual modality HSV-2 vaccine for preventing genital herpes using glycoproteins C and D subunit antigens to induce potent antibody responses and adenovirus vectors containing capsid and tegument proteins as T cell immunogens J Virol 89 (16): 8497-8509,2015.
Reid MJ, Haas M, Sedigeng P, Ramogola-Masire D, Friedman HM, Ho-Foster A: Leveraging HIV programming to enhance access to Non-Communicable Disease (NCD) care in southern Botswana Journal of the International Association of Providers of AIDS Care 15 : 7-10,2016.
Reid MJ, Biller N, Lyon SM, Reilly JP, Merlin J, Dacso M, Friedman HM: Reducing risk and enhancing education: U.S. medical students on global health electives American Journal Infection Control 42 (12): 1319-21,2014.
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 88 (15): 8421-32,2014.
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 210 (4): 571-5,2014.
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): 27-32,2014.
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