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Infection with HSV-1 produces a complex cascade of immune responses, with both the innate and adaptive arms of the immune system recruited. While the exact contribution of different cell subsets to the immune response against HSV is unknown, it appears clear that there is substantial redundancy (Kastrukoff et al., 2010). The immune response is important for restricting the acute infection with HSV-1, but it is unclear to what extent the immune response is responsible for suppressing the virus into latency. Once latency is established, the immune response to HSV-1 plays a vital part in determining the outcome following reactivation (Liu et al., 2000). Therefore, for the sake of clarity, only the immune response to acute primary HSV-1 infection will be discussed in this section, with the role of the host’s immune response during latency discussed in greater detail in Section 1.3.7. Following infection with HSV-1, an innate immune response is induced that is vital for controlling the HSV-1 replication and preventing virus spread to the central nervous system (CNS). This begins with an influx of neutrophils, though these cells probably do not play a key role in controlling infection (Stumpf et al., 2002; Wojtasiak et al., 2010). During this early stage of infection, numerous chemokines and cytokines are produced through induction of pathogen recognition receptors such as toll-like receptors (TLRs) 2, 3 and 9 (Davey et al., 2010; Rasmussen et al., 2007; Sørensen et al., 2008). These factors play an important role in attracting other immune cells to the site of infection that are able to effectively suppress local HSV-1 infection (Cheng et al., 2000; Kastrukoff et al., 2010; Shimeld et al., 1995). This suppression of virus is thought to be mediated by the interferons (IFNs), particularly IFN-α and IFN-β, produced by cells such as plasmacytoid dendritic cells, macrophages and natural killer (NK) cells (Rasmussen et al., 2007). γδ+ _T

cells also infiltrate the trigeminal ganglia (TG) of ocularly infected mice shortly after infection, but it is unknown if they significantly contribute to the control of HSV-1 (Kastrukoff et al., 2010; Kodukula et al., 1999; Liu et al., 1996; Sciammas et al., 1997). IFN-α and IFN-β have potent antiviral effects, limiting the replication and spread of virus at both the site of infection and within the nervous system, demonstrated by the enhanced virulence of HSV in IFN-receptor deficient mice following corneal infection (Leib et al., 1999). The importance of IFN-α and IFN-β for controlling HSV-1 infection is further underscored by the multiple mechanisms employed by the virus to evade this IFN response (Leib et al., 2000; Lin et al., 2004; Sanchez and Mohr, 2007). In addition, IFN-γ and tumour necrosis factor α (TNF-α) have some role in controlling viral infection, such as through the mediation of leukocyte infiltration and upregulation of major histocompatibility complex class I (MHC-I), but the overall contribution of IFN-γ to controlling HSV-1 infection is controversial (Geiger et al., 1997; Ghiasi et al., 2000; Kastrukoff et al., 2010; Kodukula et al., 1999; Leib et al., 1999; Liu et al., 1996; Tang and Hendricks, 1996; Tigges et al., 1996). Various other cytokines and antimicrobial molecules have been implicated in control of HSV-1 infection, including, but not limited to, interleukin (IL)-6, nitric oxide and IL-12 (Karupiah et al., 1993; Kodukula et al., 1999; Pasieka et al., 2009; Stumpf et al., 2002).

Ultimately it is the adaptive immune response that is required to control the virus infection and for the establishment of latency. Large numbers of CD8+ _{T cells are recruited} and produced, along with the production of large amounts of IFN-γ by CD4+ _{T cells. This is} dependent on the presentation of antigen by primed dendritic cells to CD4+ and CD8+ T cells (Allan et al., 2003; Bedoui et al., 2009; Lee et al., 2009). Using CD4+ _{T cell deficient} mice, it has been shown that CD4+ _{T cells are important for controlling HSV-1 in the} periphery, probably via the recruitment of cells such as macrophages (Manickan and Rouse, 1995). By contrast, in the nervous system CD8+ _{T cells play a more significant role} (Nash et al., 1987; Simmons and Nash, 1985; Simmons and Tscharke, 1992; Valyi-Nagy et al., 1992).

Nonspecific CD8+ _{T cell recruitment into inflamed and infected tissues occurs shortly after} infection, but subsequent accumulation, expansion and maintenance of activated CD8+ _T cells is HSV-specific (Stock et al., 2011; Van Lint et al., 2005; Wakim et al., 2008a). By transferring HSV-specific effector CD8+ _{T cells, Wakim and colleagues (2008b) found that} the presence of HSV-specific effector CD8+ _{T cells during acute infection can attenuate} primary infection. These CD8+ _{T cells do not prevent the establishment of latency within} neurons but they can dampen the skin infection and limit skin to nerve transmission,

thereby reducing the average HSV genome copy number in residual latently infected neurons Further, if activated HSV-specific CD8+ _{T cells are transferred into an immune} incompetent RAG1-/- _{mouse shortly after infection, these same cells can completely clear} ongoing lytic replication (Van Lint et al., 2004). Therefore, CD8+ _{T cells may act to clear} replicating virus after infection is well established, as well as limiting the spread of HSV-1 from the primary site of infection or to the CNS to reduce the viral genome copy number within latently infected neurons (Kastrukoff et al., 2010; Van Lint et al., 2004).

Infection with HSV-1 results in the production of a humoral immune response but it does not play a dominant role in controlling infection (Deshpande et al., 2000a). In an ocular model of HSV-1 infection, B-cell deficient mice were found to be more susceptible to herpes-induced encephalitis and keratitis, with increased viral persistence in the eye. However, these mice are also deficient in T cell mediated immune responses, and it is likely that B cells primarily function as regulators of the T cell response in the context of HSV-1 infection by presenting antigen or producing cytokines (Deshpande et al., 2000b). It has also been shown that antibodies against HSV can mediate prophylactic protection in mice, but this is dependent on high concentrations of antibody or sera that far exceed normal physiological levels following HSV-1 infection of mice. For example, it has also been shown that the administration of a monoclonal antibody can protect nude mice against subsequent HSV-1 infection (Sanna et al., 1996). In addition, the administration of subunit vaccines designed to elicit antibody responses directed against HSV-1 glycoproteins resulted in high neutralising antibody titres that were protective against subsequent lethal challenges of HSV-1 in mice (Ghiasi et al., 1994). So, the induction of a strong humoral immune may be able to mediate protection from HSV-1 infection in a vaccine context, but the humoral immune response does not appear to significantly influence the course of a natural HSV-1 infection.