A Locus on Mouse Chromosome 6 That Determines Resistance to Herpes Simplex Virus Also Influences Reactivation, While an Unlinked Locus Augments Resistance of Female Mice

Viral fitness dictates virulence and capacity to evade host immune defenses. Understanding the biological underpinnings of such features is essential for rational vaccine development. We have previously shown that the live-attenuated herpes 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 vitro and functions as a highly efficacious experimental vaccine. Here, we characterize the host immune response and in vivo pathogenesis of HSV-1 0ΔNLS relative to its fully virulent parental strain in C57BL/6 mice. Additionally, we explore the role of type 1 interferon (IFN-␣/␤) signaling on virulence and immunogenicity of HSV-1 0ΔNLS and uncover a probable sex bias in the induction of IFN-␣/␤ in the cornea during HSV-1 infection. Our data show that HSV-1 0ΔNLS lacks neurovirulence even in highly immunocompromised mice lacking the IFN-␣/␤ receptor. These studies support the translational viability of the HSV-1 0ΔNLS vaccine strain by demonstrating that, while it is comparable to a virulent parental strain in terms of immunogenicity, HSV-1 0ΔNLS does not induce significant tissue pathology.IMPORTANCE HSV-1 is a common human pathogen associated with a variety of clinical presentations ranging in severity from periodic "cold sores" to lethal encephalitis. Despite the consistent failures of HSV subunit vaccines in clinical trials spanning the past 28 years, opposition to live-attenuated HSV vaccines predicated on unfounded safety concerns currently limits their widespread acceptance. Here, we demonstrate that a live-attenuated HSV-1 vaccine has great translational potential.KEYWORDS HSV-1, T cells, antibody, cornea, mouse, neovascularization S trategies for vaccine development have transitioned largely from empirical to so-called "next-generation" or rational approaches during the past 2 decades, a shift largely driven by technological advances and a better understanding of how innate immunity influences the generation of adaptive protection (1, 2). Despite these breakthroughs, the average person still acquires multiple herpesvirus infections during childhood (3). A licensed vaccine, however, exists only for varicella-zoster virus (VZV) (4). The live-attenuated Oka vaccine for VZV is generally well tolerated and has significantly reduced the incidence of VZV infection, morbidity, and mortality in the United States (5, 6). Furthermore, epidemiologic studies indicate that acquisition of herpes simplex virus 1 (HSV-1) has shifted toward early to late adolescence in recent decades within the United States, potentially creating an opportunity to introduce an effective prophylactic HSV-1 vaccine into the childhood vaccine regimen (7). HSV vaccines have been tested in multiple clinical trials, but these studies have focused on protein subunit vaccines

supporting

confidence: 77%

Impact of Type I Interferon on the Safety and Immunogenicity of an Experimental Live-Attenuated Herpes Simplex Virus 1 Vaccine in Mice

Royer

Carr

Chucair-Elliott

et al. 2017

“…The antiviral effects of TNF on two poxviruses, vaccinia virus and ectromelia virus, were shown to depend on both p55 and p75 TNF receptors (56). However, we have reported that C57BL/6 and p55 Ϫ/Ϫ p75 Ϫ/Ϫ mortality rates were indistinguishable, ranging from 13% to 15% (P Ͼ 0.05) in HSV-1-infected mice (43). These results imply that while TNF is required for protection against fatal HSV-1 infection, both p55 and p75 receptors are dispensable.…”

Section: Discussionmentioning

confidence: 63%

“…We have previously shown that B6 mice lacking either or both TNF receptors are as resistant to fatal HSE as are B6 control mice (43). However, a protective role for TNF is suggested by results showing that intraperitoneal administration of TNF can protect against fatal HSE (55).…”

Section: Resultsmentioning

confidence: 81%

Tumor Necrosis Factor (TNF) Protects Resistant C57BL/6 Mice against Herpes Simplex Virus-Induced Encephalitis Independently of Signaling via TNF Receptor 1 or 2

Lundberg¹,

Welander²,

Edwards

et al. 2007

Self Cite

Tumor necrosis factor (TNF) is a multifunctional cytokine that has a role in induction and regulation of host innate and adaptive immune responses. The importance of TNF antiviral mechanisms is reflected by the diverse strategies adopted by different viruses, particularly members of the herpesvirus family, to block TNF responses. TNF binds and signals through two receptors, Tnfrsf1a (TNF receptor 1 [TNFR1], or p55) and Tnfrsf1b (TNFR2, or p75). We report here that herpes simplex virus 1 (HSV-1) infection of TNF ؊/؊ mice on the resistant C57BL/6 genetic background results in significantly increased susceptibility (P < 0.0001, log rank test) to fatal HSV encephalitis (HSE) and prolonged persistence of elevated levels of virus in neural tissues. In contrast, although virus titers in neural tissues of p55 ؊/؊ N13 mice were elevated to levels comparable to what was found for the TNF ؊/؊ mice, the p55 ؊/؊ N13 mice were as resistant as control C57BL/6 mice (P > 0.05). The incidence of fatal HSE was significantly increased by in vivo neutralization of TNF using soluble TNFR1 (sTNFR1) or depletion of macrophages in C57BL/6 mice (P ‫؍‬ 0.0038 and P ‫؍‬ 0.0071, respectively). Strikingly, in vivo neutralization of TNF in HSV-1-infected p55 ؊/؊ p75 ؊/؊ mice by use of three independent approaches (treatment with soluble p55 receptor, anti-TNF monoclonal antibody, or in vivo small interfering RNA against TNF) resulted in significantly increased mortality rates (P ‫؍‬ 0.005), comparable in magnitude to those for C57BL/6 mice treated with sTNFR1 (P ‫؍‬ 0.0018). Overall, these results indicate that while TNF is required for resistance to fatal HSE, both p55 and p75 receptors are dispensable. Precisely how TNF mediates protection against HSV-1 mortality in p55 ؊/؊ p75 ؊/؊ mice remains to be determined.Early innate and subsequent adaptive immune responses to viral and bacterial pathogens are critically dependent on the tumor necrosis factor (TNF) superfamily of cytokines. These TNF superfamily cytokines act as effectors of host defense and regulate peripheral lymphoid tissue organogenesis and differentiation of natural killer cells and lymphoid cells (42,46). TNF, a multifunctional cytokine produced primarily by activated macrophages (70), functions as a key regulator of leukocyte trafficking by affecting chemokine expression and stimulating antigen presentation, which it does by inducing dendritic cell maturation (26, 58). TNF exists in two forms, a precursor 26-kDa membrane-bound form (mTNF) and a 17-kDa soluble form (sTNF), both of which are bioactive (46, 71). TNF and the closely related ligand lymphotoxin-␣ (LT) bind as homotrimers to two receptors, TNF receptor 1 (TNFR1, or p55) and TNFR2 (p75), which are widely expressed on most cell types (71). Activation of p55 generally results in gene activation that leads to induction of inflammatory and cytotoxic responses, while activation of TNFR2 is associated with thymocyte proliferation and T-cell activation. In response to TNF binding, lipopolysaccharide (LPS) and several other s...

“…The C3 knockout mice are in a C57BL/6 background; therefore, C57BL/6 mice were used as controls. A higher-titer inoculum (5 ϫ 10 6 PFU) was used for these experiments, since C57BL/6 mice are more resistant than BALB/c mice to HSV-1 infection (33,36). C57BL/6 (complement-sufficient) mice were passively immunized with 200 g of human IgG antibody to HSV or nonimmune human IgG 20 h prior to flank infection with NS-gE264.…”

Section: Vol 85 2011 Immune Evasion Mediated By the Hsv-1 Igg Fc Rementioning

confidence: 99%

The Herpes Simplex Virus 1 IgG Fc Receptor Blocks Antibody-Mediated Complement Activation and Antibody-Dependent Cellular CytotoxicityIn Vivo

Lubinski

Lazear

Awasthi

et al. 2011