Mucosal herpes immunity and immunopathology to ocular and genital herpes simplex virus infections

Abstract

Herpes simplex viruses type 1 and type 2 (HSV-1 and HSV-2) are amongst the most common human infectious viral pathogens capable of causing serious clinical diseases at every stage of life, from fatal disseminated disease in newborns to cold sores genital ulcerations and blinding eye disease. Primary mucocutaneous infection with HSV-1 & HSV-2 is followed by a lifelong viral latency in the sensory ganglia. In the majority of cases, herpes infections are clinically asymptomatic. However, in symptomatic individuals, the latent HSV can spontaneously and frequently reactivate, reinfecting the muco-cutaneous surfaces and causing painful recurrent diseases. The innate and adaptive mucosal immunities to herpes infections and disease remain to be fully characterized. The understanding of innate and adaptive immune mechanisms operating at muco-cutaneous surfaces is fundamental to the design of next-generation herpes vaccines. In this paper, the phenotypic and functional properties of innate and adaptive mucosal immune cells, their role in antiherpes immunity, and immunopathology are reviewed. The progress and limitations in developing a safe and efficient mucosal herpes vaccine are discussed.

Figure 1

Model of immune mechanisms of TLR2-mediated control of an anti-HSV-1 immune response in the conjunctiva. During topical ocular immunization with TLR2 agonist (1), high concentration of exogenous TLR2 agonist is sensed by conjunctiva APC and Treg cells residing in the epithelium and then triggers the migration of conjunctiva resident APC (DC) and Treg to the proximal draining lymph node (2, 4) or (dashed arrow) to the conjunctiva lymphoid follicles (CLF). TLR2/TLR2L interaction promotes maturation of DC and proliferation of Tregs paralleled by temporarily abrogated suppression (empty arrow). As a result, Tregs do not suppress the ongoing immune response in the draining lymph node or in CLF. (3) DC stimulate naïve CD4+ and CD8+ effector T cells which undergo cell division and proliferation in the draining LN (5) or CLF where they form with B cells a germinal center (characteristic of lymphoid follicles). Activated effector T cells migrate to the epithelium and kill HSV-1-infected epithelial cells through CTL activity. Some activated effector cells in the LN preferentially migrate to the periphery through lymphoid afferent canal to induce systemic immune response. Once HSV-1 is cleared by the immune system and the source of TLR2 ligands is no longer present, Tregs will regain their suppressive capabilities, thus contributing to the balance between tolerance and immunity.

Figure 2

A model of CD8⁺ T-cell monitoring of HSV-1 latency in sensory ganglia. (a) During a primary infection (affecting the cornea of the eye), HSV-1 invades the termini of sensory neurons, the nucleocapsid travels by retrograde axonal transport to the neuron cell bodies within the trigeminal ganglion (TG), viral DNA is inserted into the nucleus, and a brief period of virus replication ensues (b). An initial infiltration of macrophages and T cells gives rise to an infiltrate dominated by CD4+ and CD8+ T cells and macrophages that persists for the life of the animal (c). The CD8+ T cells associate closely with the neuron cell bodies and directly monitor viral gene expression in neurons by detecting epitopes of viral epitopes that are produced early in a reactivation event and presented on the surface of the neuron within MHC class I. The CD8+ T cells force the viral genome into a quiescent state through IFN-γ production (early in reactivation) or through the release of lytic granules (at later stages of reactivation). A similar model can be extrapolated to genital herpes infection with HSV-2.

Figure 3

A model of CD8⁺ T-cell exhaustion and HSV-1 reactivation from sensory ganglia. During reactivation, the virus travels from the TG back to the cornea and causes eruptions of epithelial surfaces (viral shedding). Viral reactivation may be asymptomatic or may be associated with symptoms or lesions [, –79]. This reactivation event may be spontaneous, but it is generally believed to be triggered by stress stimuli and immunosuppressive conditions. CD8+ T-cell function is compromised (e.g., by stress-related hormones), viral glycoproteins and nucleocapsids are formed and transported by anterograde axonal transport, virions are assembled at nerve termini, and infectious virus is released, potentially leading to recurrent disease. Evidence from our laboratory and others suggested that latently infected neurons appear to be resistant to CD8+ T-cell-mediated killing and that LAT is involved in this resistance to CD8+ T-cell killing. Recently, we found that neuroblastoma cells expressing LAT in the absence of other HSV-1 genes resisted to GrB-induced apoptosis and are protected from CD8+ T-cells attack. Also, latently infected TG have high expression of PDL-1 and Gal9 on infected neuronal cells also the majority of CD8+ T-cells surrounding neuronal cells express high PD-1 and Tim3.

Figure 4

Blockade of T-cell inhibitory pathways to boost immunity to herpes simplex virus infections. Multiple inhibitory pathways may be activated in the exhausted CD8+ T cells in the HSV-1 latently infected TG, including PD-1, TIM-3, and LAG-3. Blockade of one T-cell inhibitory pathway may partially restore HSV-specific CD8+ T-cell effector functions. Blocking antibodies may be directed against the PD-1, TIM-3 and LAG-3 T-cell inhibitory receptors on CD8+ T cells or possibly their ligands (PD-L1 galectin-9 and MHC-II, resp.) on infected neurons or on DC. Full restoration of CD8+ T-cell function may require blockade of two or more inhibitory pathways or a combination of pathway blockade and vaccination. Sustained restoration of DC maturation may be also crucial for functional CD8+ T-cell function and clinical cure. HSV-1 LAT gene appears-interfering with both CD8+ T-cell function and with DC maturation. How CD8+ T cells are dysfunctional and DC are silenced, and the pathways to rescue this silencing, is still unknown.