If you like to watch video lectures and read scientific papers, you will enjoy this section. Below are links to Dr. Halford's work and research on the herpes simplex virus, spanning over the last 20 years.
These are all the reasons I have a story to tell.
Dr. William Halford
EDUCATION: B.S. Marine Biology and Microbiology, University of California, Santa Barbara (1986-91); Ph.D. Viral Immunology, Louisiana State University HSC, New Orleans (1992-96); Postdoctoral fellow, Molecular Virology, University of Pennsylvania, Philadelphia (1997-2000) FACULTY APPOINTMENTS: Assistant Professor of Microbiology and Immunology, Tulane University School of Medicine, New Orleans (2000-2004); Assistant Professor of Veterinary Molecular Biology, Montana State University, Bozeman (2004-2007); Associate Professor of Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield (2007 - present)
Dr Halford passed away on June 22, 2017
Impact of Type I Interferon on the Safety and Immunogenicity of an Experimental Live-Attenuated Herpes Simplex Virus 1 Vaccine in Mice
Viral fitness dictates virulence and capacity to evade host immune de-fenses. Understanding the biological underpinnings of such features is essential forrational vaccine development. We have previously shown that the live-attenuatedherpes simplex virus 1 (HSV-1) mutant lacking the nuclear localization signal (NLS)on the ICP0 gene (0ΔNLS) is sensitive to inhibition by interferon beta (IFN-)in vitroand functions as a highly efficacious experimental vaccine. Here, we characterize thehost immune response andin vivopathogenesis of HSV-1 0ΔNLS relative to its fullyvirulent parental strain in C57BL/6 mice. Additionally, we explore the role of type 1interferon (IFN-/) signaling on virulence and immunogenicity of HSV-1 0ΔNLS anduncover a probable sex bias in the induction of IFN-/in the cornea during HSV-1infection. Our data show that HSV-1 0ΔNLS lacks neurovirulence even in highly im-munocompromised mice lacking the IFN-/receptor. These studies support thetranslational viability of the HSV-1 0ΔNLS vaccine strain by demonstrating that, whileit is comparable to a virulent parental strain in terms of immunogenicity, HSV-10ΔNLS does not induce significant tissue pathology
A Highly Efficacious Herpes Simplex Virus 1 Vaccine Blocks Viral Pathogenesis and Prevents Corneal Immunopathology via Humoral Immunity
Correlates of immunologic protection requisite for an efficacious herpes simplex virus 1 (HSV-1) vaccine remain unclear with respect to viral pathogenesis and clinical disease. In the present study, mice were vaccinated with a novel avirulent, live attenuated virus (0NLS) or an adjuvanted glycoprotein D subunit (gD-2) similar to that used in several human clinical trials. Mice vaccinated with 0NLS showed superior protection against early viral replication, neuroinvasion, latency, and mortality com-pared to that of gD-2-vaccinated or naive mice following ocular challenge with a neurovirulent clinical isolate of HSV-1. More-over, 0NLS-vaccinated mice exhibited protection against ocular immunopathology and maintained corneal mechano sensoryfunction. Vaccinated mice also showed suppressed T cell activation in the draining lymph nodes following challenge. Vaccine efficacy correlated with serum neutralizing antibody titers. Humoral immunity was identified as the correlate of protection against corneal neovascularization, HSV-1 shedding, and latency through passive immunization. Overall, 0NLS affords remarkable protection against HSV-1-associated ocular sequelae by impeding viral replication, dissemination, and establishment of latency.
Antibodies Are Required for CompleteVaccine-Induced Protection against HerpesSimplex Virus 2
Herpes simplex virus 2 (HSV-2) 0ΔNLS is a live HSV-2ICP0-mutant vaccine strain that is profoundly attenuated invivo due to its interferon-hypersensitivity. Recipients of the HSV-20ΔNLS vaccine are resistant to high-dose HSV-2 challenge as evidenced by profound reductions in challenge virus spread, shedding, disease and mortality. In the current study,we investigated the requirements for HSV-2 0ΔNLS vaccine-induced protection. Studies using (UV)-inactivated HSV-2 0ΔNLS revealed that self-limited replication of the attenuated virus was required for effective protection from vaginal or ocular HSV-2 challenge.
Herpes Simplex Virus 2 (HSV-2) Infected CellProteins Are among the Most DominantAntigens of a Live-Attenuated HSV-2 Vaccine
Virion glycoproteins such as glycoprotein D (gD) are believed to be the dominant antigens of herpes simplex virus 2 (HSV-2). We have observed that mice immunized with a liveHSV-2ICP0-mutant virus, HSV-2 0ΔNLS, are 10 to 100 times better protected against genital herpes than mice immunized with a HSV-2 gD subunit vaccine (PLoS ONE6:e17748). Inlight of these results, we sought to determine which viral proteins were the dominant anti-body-generators (antigens) of the live HSV-2 0ΔNLS vaccine. Western blot analyses indicated the live HSV-2 0ΔNLS vaccine elicited an IgG antibody response against 9 or more viral proteins.
Pan-HSV-2 IgG Antibody in Vaccinated Mice and GuineaPigs Correlates with Protection against Herpes SimplexVirus 2
We lack a correlate of immunity to herpes simplex virus 2 (HSV-2) that may be used to differentiate whether a HSV-2 vaccine elicits robust or anemic protection against genital herpes. This gap in knowledge is often attributed to a failure to measure the correct component of the adaptive immune response to HSV-2. However, efforts to identify a correlate of immunity have focused on subunit vaccines that contain less than 3% of HSV-2’s 40,000-amino-acid proteome. We were interested to determine if a correlate of immunity might be more readily identified if1.animals were immunized with apolyvalent immunogen such as a live virus and/or2.the magnitude of the vaccine-induced immune response was gauged in terms of the IgG antibody response to all of HSV-2’s antigens (pan-HSV-2 IgG). Pre-challenge pan-HSV-2 IgG levels and protection against HSV-2 were compared in mice and/or guinea pigs immunized with a gD-2 subunit vaccine, wild-type HSV-2, or oneof several attenuated HSV-2ICP02viruses (0D254, 0D810, 0DRING, or 0DNLS). These six HSV-2 immunogens elicited a wide range of pan-HSV-2 IgG levels spanning an,500-fold range. For 5 of the 6 immunogens tested, prechallenge levels of pan-HSV-2 IgG quantitatively correlated with reductions in HSV-2 challenge virus shedding and increased survival frequency following HSV-2 challenge. Collectively, the results suggest that pan-HSV-2 IgG levels may provide a simple and useful screening tool for evaluating the potential of a HSV-2 vaccine candidate to elicit protection against HSV-2 genital herpes.
A Live-Attenuated HSV-2ICP02Virus Elicits 10 to 100Times Greater Protection against Genital Herpes than aGlycoprotein D Subunit Vaccine
Glycoprotein D (gD-2) is the entry receptor of herpes simplex virus 2 (HSV-2), and is the immunogen in the pharmaceutical industry’s lead HSV-2 vaccine candidate. Efforts to prevent genital herpes using gD-2 subunit vaccines have been on going for 20 years at a cost in excess of$100 million. To date, gD-2 vaccines have yielded equivocal protection in clinical trials.Therefore, using a small animal model, we sought to determine if a live-attenuated HSV-2ICP02virus would elicit better protection against genital herpes than a gD-2 subunit vaccine. Mice immunized with gD-2 and a potent adjuvant(alum+monophosphoryl lipid A) produced high titers of gD-2 antibody. While gD-2-immunized mice possessed significant resistance to HSV-2, only 3 of 45 gD-2-immunized mice survived an overwhelming challenge of the vagina or eyes with wild-type HSV-2 (MS strain). In contrast, 114 of 115 mice immunized with a live HSV-2ICP02virus, 0DNLS, survived the same HSV-2 MS challenges. Likewise, 0DNLS-immunized mice shed an average 125-fold less HSV-2 MS challenge virus per vagina relative to gD-2-immunized mice.In vivo imaging demonstrated that a luciferase-expressing HSV-2 challenge virus failed toestablish a detectable infection in 0DNLS-immunized mice, whereas the same virus readily infected naı ̈ve and gD-2-immunized mice. Collectively, these results suggest that a HSV-2 vaccine might be more likely to prevent genital herpes if itcontained a live-attenuated HSV-2 virus rather than a single HSV-2 protein.
Herpes Simplex Virus 2ICP02Mutant Viruses AreAvirulent and Immunogenic: Implications for a GenitalHerpes Vaccine
Herpes simplex virus 1 (HSV-1)ICP02mutants are interferon-sensitive, avirulent, and elicit protective immunity against HSV-1(Virol J, 2006, 3:44). If anICP02mutant of herpes simplex virus 2 (HSV-2) exhibited similar properties, such a virus might be used to vaccinate against genital herpes. The current study was initiated to explore this possibility. Several HSV-2ICP02mutant viruses were constructed and evaluated in term of three parameters:i.interferon-sensitivity;ii.virulence in mice;andiii.capacity to elicit protective immunity against HSV-2. OneICP02mutant virus in particular, HSV-2 0DNLS, achieved anoptimal balance between avirulence and immunogenicity. HSV-2 0DNLS was interferon-sensitive in cultured cells. HSV-20DNLS replicated to low levels in the eyes of inoculated mice, but was rapidly repressed by an innate, Stat 1-dependent hostimmune response. HSV-2 0DNLS failed to spread from sites of inoculation, and hence produced only inapparent infections.Mice inoculated with HSV-2 0DNLS consistently mounted an HSV-specific IgG antibody response, and were consistently protected against lethal challenge with wild-type HSV-2. Based otheir avirulence and immunogenicity, we propose that HSV-2 ICP02mutant viruses merit consideration for their potential to prevent the spread of HSV-2 and genital herpes
Part 1 - An Introduction to the α-Herpesviruse and a very in-depth look into the behavior of Herpes simplex.
Part 2 of Dr. Halford's Lecture on Herpes simplex. Also he discusses the many evasion strategies of herpes simplex and why it continues reinfect many people.
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