Herpes simplex viruses are ubiquitous human pathogens represented by two distinct serotypes: herpes simplex virus (HSV) type 1 (HSV-1); and HSV type 2 (HSV-2). In the general population, adult seropositivity rates approach 90% for HSV-1 and 20-25% for HSV-2. These viruses cause significant morbidity, primarily as mucosal membrane lesions in the form of facial cold sores and genital ulcers, with much less common but more severe manifestations causing death from encephalitis. HSV infections in humans are difficult to study in many cases because many primary infections are asymptomatic. Moreover, the neurotropic properties of HSV make it much more difficult to study the immune mechanisms controlling reactivation of latent infection within the corresponding sensory ganglia and crossover into the central nervous system of infected humans. This is because samples from the nervous system can only be routinely obtained at the time of autopsy. Thus, animal models have been developed whose use has led to a better understanding of multiple aspects of HSV biology, molecular biology, pathogenesis, disease, and immunity. The course of HSV infection in a spectrum of animal models depends on important experimental parameters including animal species, age, and genotype; route of infection; and viral serotype, strain, and dose. This review summarizes the animal models most commonly used to study HSV pathogenesis and its establishment, maintenance, and reactivation from latency. It focuses particularly on the immune response to HSV during acute primary infection and the initial invasion of the ganglion with comparisons to the events governing maintenance of viral latency.

The role of CD4؉ helper T cells in modulating the acquired immune response to herpes simplex virus type 1 (HSV-1) remains ill defined; in particular, it is unclear whether CD4 ؉ T cells are needed for the generation of the protective HSV-1-specific CD8؉ -T-cell response. This study examined the contribution of CD4 ؉ T cells in the generation of the primary CD8؉ -T-cell responses following acute infection with HSV-1. The results demonstrate that the CD8 ؉ -T-cell response generated in the draining lymph nodes of CD4 ؉ -T-cell-depleted C57BL/6 mice and B6-MHC-II ؊/؊ mice is quantitatively and qualitatively distinct from the CD8 ؉ T cells generated in normal C57BL/6 mice. Phenotypic analyses show that virus-specific CD8 ؉ T cells express comparable levels of the activation marker CD44 in mice lacking CD4 ؉ T cells and normal mice. In contrast, CD8؉ T cells generated in the absence of CD4 ؉ T cells express the interleukin 2 receptor ␣-chain (CD25) at lower levels. Importantly, the CD8 ؉ T cells in the CD4؉ -T-cell-deficient environment are functionally active with respect to the expression of cytolytic activity in vivo but exhibit a diminished capacity to produce gamma interferon and tumor necrosis factor alpha. Furthermore, the primary expansion of HSV-1-specific CD8 ؉ T cells is diminished in the absence of CD4؉ -T-cell help. These results suggest that CD4 ؉ -T-cell help is essential for the generation of fully functional CD8 ؉ T cells during the primary response to HSV-1 infection.

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Herpes simplex virus type 1 (HSV-1) is a ubiquitous human pathogen capable of causing fatal encephalitis in rare instances. The immediate recognition of the virus by pattern recognition receptors at the infection site is crucial for establishing an antiviral state and limiting nervous system involvement. The importance of TLR3 and TLR9 in the type I interferon-dependent protection against HSV disease has been well documented, however, the role of TLR2 is less clear. This study aims to define the function of TLR2 in a natural infection model of mucocutaneous HSV-1 disease. TLR2 is expressed on the cell surface of various cell types, and ligation leads to an NF-B-dependent inflammatory response. Here we demonstrate that Tlr2-/- mice are significantly more susceptible to HSV-1 disease than WT controls. Whereas Tlr2-/- mice have indistinguishable levels of infectious virus at the inoculation site, the deficient animals display faster nervous system invasion and elevated viral loads in the trigeminal ganglia, brainstem, and brain, indicating that TLR2-expressing cells in the nervous system aid in controlling HSV-1 replication and spread. Mortality from HSV-1 CNS infection is the result of virus-mediated cytotoxicity in combination with the ensuing neuroinflammatory response. We are currently assessing the magnitude and kinetics of CNS inflammation as well as the activation and infiltration of immune cells to the CNS in order to delineate the mechanism of TLR2 protection.

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