The role of the immune response in controlling HSV infections is multi-faceted and complex. This complexity is a function, in part, of HSV being distributed in both neuronal and extraneuronal sites during the primary and latent stages of infection. In addition, HSV persists within the host even in the presence of concomitant immunity by establishing itself as a latent infection within sensory neurons that innervate the sites of peripheral infection. Despite these challenges, considerable progress has been made in defining the immune components that play a key role in the resolution of an HSV infection and, in the case of adaptive immune responses, in identifying the specific virus-encoded epitopes that are recognized by the B and T lymphocytes. Because a comprehensive discussion of the immune response to HSV infections is beyond the scope to this chapter, the reader is directed to recent reviews on this topic for more detailed information (Koelle and Corey, 2003; Khanna et al., 2004).
7. Stress, Immune Response, and HSV Pathogenesis 127 1.2.1. Innate and Adaptive Immunity
Both the innate and adaptive arms of the immune response have been shown to play a role in immunity to HSV in both immune and naïve individuals. Furthermore, both arms have been shown to function not only at the site of the primary infection in the periphery but also in the initial control of HSV-1 replication in the sensory ganglia and the establishment of a latent infection. Although the immune response at the primary site of HSV infection has been well characterized, less has been known about the immunological events that occur in the sensory ganglia during latency. However, as described below, there is recent evidence of a role for T lymphocytes in controlling HSV-1 latency (Liu et al., 2000; Khanna et al., 2003, 2004). Such findings have challenged the long-held view that HSV is able to "hide" from the immune system during latency and suggest that the immune system controls recurrent herpetic disease both during active infection in the periphery and during latent infection in the nervous system. Latency represents the stage of infection during which stress, in part, may be associated with HSV reactivation and recurrent disease.
The innate immune system possesses two primary functions in mediating a defense against pathogenic microorganisms: the direct destruction of the pathogens and the initiation of specific types of adaptive immunity that will follow. Studies in both humans and animals have been valuable in deciphering the components of the innate immune response that play important roles in defense against HSV. Innate immune components that are elicited in response to HSV-1 infection include: the activation of the complement cascade; the activation of macrophages; and the recruitment, activation, and maturation of natural killer (NK) cells, dendritic cell precursors, and y/8 extrathymic-derived T cells. Activation of the innate immune response also results in the generation and secretion of a variety of cytokines and chemokines that orchestrate the above activities. These responses are designed to limit the initial infection and to abrogate further virus propagation. As equally important is the role of these responses in the generation of the adaptive immune response, which is comprised of the activation of both HSV-specific helper and cytotoxic T cells as well as the maturation of B cells for HSV-specific antibody production.
The adaptive immune response to HSV infection has been shown to play a key role in primary and, more recently, in latent HSV infections. The production of HSV-specific antibodies has been known for quite some time. These antibodies function in both a virus neutralizing capacity as well as in conjunction with other cell types (e.g., polymorphonuclear leukocytes, monocytes, and NK-like cells) in mediating antibody-dependent cellmediated cytotoxicity (ADCC).There is also compelling evidence that antibody alone is able to provide protection in neonates exposed to HSV at or near the time of birth (Brown et al., 1991). However, despite the presence of high levels of circulating HSV-specific antibodies in latently infected adults, HSV reactivation and recrudescent herpetic disease appear to go unchecked. More recently, a number of studies have focused on the specific roles of CD4+ and CD8+ T lymphocytes in anti-HSV immunity and the specificity of these T-lymphocyte responses. There are several lines of evidence indicating that both of these subsets of T lymphocytes are functionally important in controlling HSV infections. CD8+ T cells mediate their protective ability via their cytotoxic effects on virus-infected target cells and their synthesis of cytokines—cytokines that may be able to inhibit viral replication. The recent finding of a role for CD8+ T cells for controlling HSV reactivation in latently infected ganglia (Khanna et al., 2003,2004) is intriguing since it was once thought that latently infected cells were essentially hidden from immunosurveillance mechanisms. CD4+ T cells are important in that they release numerous cytokines that can both orchestrate the inflammatory response that is associated with HSV infection as well as play a key role in determining the magnitude of the CD8+ T-cell response. Overall, components of the adaptive immune response have the potential to control HSV infections and thus may form the basis for the development of an effective anti-HSV vaccine.
An individual who has previously recovered from a primary HSV infection exhibits an adaptive immune response upon HSV reinfection that differs primarily in its rapidity and magnitude as compared with an individual who has never been infected. Given the relative insignificance of high titers of HSV-specific antibody in the development of recurrent herpetic diseases in adults, most attention has focused on memory T lymphocyte responses, particularly the cytotoxic T lymphocyte (CTL) responses.
Memory cytotoxic T lymphocytes (CTLm) play an important role in mediating long-term protective immunity against a variety of intracellular pathogens (reviewed in Doherty et al., 1992; Sher and Coffman, 1992; Gray, 1993; Mackay, 1993; Pamer, 1993; Ahmed, 1994; Sprent, 1994). Although these CTLm do not prevent recurrence or reinfection per se, they do limit the severity of infection/disease by becoming activated in an accelerated fashion following reexposure to the particular pathogen (Gray, 1993; Mackay, 1993;Ahmed, 1994; Sprent, 1994).This activation occurs as memory T cells move continually from blood to tissues, scanning cell surfaces for the appropriate antigen to which they are programmed to recognize. Upon an encounter with this antigen, CTLm are readily triggered to become effector CTL. In the case of viral infections, the encounter of the CTLm with a virus-specific antigen triggers these memory CTL to proliferate rapidly, differentiate into effector cells, and localize to the site of infection. It is here where these CTL destroy virus-infected cells, thus eliminating the virus "factories" that produce infectious viral progeny. These CTL also synthesize cytokines such as IFN-y and TNF-a that have both a direct antiviral activity as well as the ability to enhance components of antigen processing and presentation.
A role of CTLm in mediating protection against recurrent HSV infections has been documented in both humans and in animals (Schmid and Rouse, 1992; Rinaldo and Torpey, 1993; Ashley et al, 1994; Koelle et al., 1998). Although HSV reactivation occurs quite frequently, it usually does not lead to an apparent clinical infection (Wald et al., 1995,1997) especially when the immune system is intact. Our knowledge of CTL-mediated defense against HSV has grown significantly. This knowledge, driven by advances in experimental immunology, has provided a solid foundation on which to decipher the mechanisms underlying the impact of stress on the immunity to HSV and to other viral infections.
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