Evidence for the role of different aspects of the immune response in the CNS in herpes virus infections comes from clinical studies and in vivo or in vitro experimental models. Natural killer (NK) cell knockout mice or NK cell–depleted mice are susceptible to HSV-induced lesions in the CNS (Nandakumar et al., 2008). Chemokines regulate leukocyte trafficking to inflamed tissues and play a crucial role in orchestrating the immune response to HSV1 infection. Control of viral infections is associated with production of CXCR3 and CCR5 agonists and recruitment of leukocytes bearing these receptors. However, single knockouts of CXCR3 and CCR5 exhibit a mild phenotype when compared to ablation of leukocyte subsets associated with these receptors, suggesting functional redundancy between these two and most likely other chemokine receptors (Wuest and Carr, 2008). Intercellular adhesion molecule-5 (ICAM5), an immune modulator in the CNS, interacts with neurovirulence factor UOL as higher numbers of lymphocytes, but unaltered soluble ICAM5 and chemokine levels, were detected in ΔUOL HSV1-infected mouse brains. This suggests that ICAM5 plays a critical role in modulating chemokine production in the CNS (Tse et al., 2009).

Humans and mice lacking signal transducer and activator of transcription-1 (STAT1) display increased susceptibility to HSV CNS infection (Pasieka et al., 2011), while STAT4 has been shown to regulate antiviral interferon gamma (IFNγ) responses and disease severity during chronic HSV2 infections in humans (Svensson et al., 2012). IFN lambda (IFNλ), a newly identified member of the IFN family (Kotenko et al., 2003), has also been shown to have the ability to inhibit HSV1 infection of primary human astrocytes and neurons. Furthermore, IFNλ treatment of astrocytes and neurons inhibits or reduces suppressor of cytokine signalling-1 (SOCS1), a key negative regulator of the IFN pathway (Li et al., 2011), which leads to increased IFN production.

Viral immune evasion has also been extensively studied with HSV. HSV1 glycoprotein E (gE) mediates cell-to-cell spread and functions as an immunoglobulin (IgG) Fc receptor (FcγR) that blocks the Fc domain of antibody targeting the virus or infected cell thus blocking both IgG Fc-mediated complement activation and antibody-dependent cellular cytotoxicity against the virus (Lubinski et al., 2011) Therefore, gE promotes immune evasion from IgG Fc-mediated activities and probably contributes to virulence when antiviral antibody is present, such as during recurrent infections. HSV1 has been found to decrease immune cell types by causing apoptosis. The virus induces de novo expression of Fas L on the cell surface and causes the death of interacting human CD4⁺ T cells, CD8⁺ T cells and NK cells (Iannello et al., 2011).

Immune suppression functions of specific virus proteins have also been identified. The HSV1-encoded glycoprotein B (gB) manipulates the MHC class II processing pathway by perturbing endosomal sorting and trafficking of HLA-DR molecules (Temme et al., 2010). Furthermore, the viral proteins gC and gE have been shown to provide a shield against neutralizing antibodies that interfere with the interaction of the virus glycoproteins gB, gD and gH–gL. Fusion of the virus envelope with the cell plasma membrane, necessary for virus entry, is dependent on interaction of these four viral glycoproteins. The HSV1 latency-associated transcript (LAT) also appears to play a role in immune evasion. Using LAT(+) and LAT(−) infected mice, results were obtained which suggest a novel immune evasion mechanism whereby the HSV1 LAT increases the number of HSV1 antigen–positive dendritic cells (DCs) in latently infected trigeminal ganglia, and interferes with DC phenotypic and functional maturation (Chentoufi et al., 2012).

HCMV may persist by evasion of immune reactions which promote virus clearance. The viral glycoprotein UL141 targets the tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) death receptors preventing apoptosis of infected cells (Smith et al., 2013). Viral immune evasion of antigen presentation by both MHC class I and II molecules occurs; by restricting the presentation of viral antigens during both productive and latent infection, HCMV limits elimination by the human immune system (Noriega et al., 2012; Hesse et al., 2013). HCMV encodes homologues of cellular cytokines and chemokines and their receptors, which facilitates viral evasion of immune clearance (McSharry et al., 2012).

The EBV genes, BCRF1 and BNLF2a, encode the viral homologue of interleukin-10 (IL10) (vIL10) and an inhibitor of the transporter associated with antigen processing (TAP), respectively. Both of these factors are known immune-evasins in the lytic phase of EBV infection. vIL10 impairs NK cell–mediated killing of infected B cells, interferes with CD4⁺ T cell activity and modulates cytokine responses. BNLF2a reduces antigen presentation and recognition of newly infected cells by EBV-specific CD8⁺ T cells. Together, both factors significantly diminish the immunogenicity of EBV-infected cells during the initial, early phase of infection before latency is established. This may also reduce recognition of infected B cells in the CNS (Jochum et al., 2012).

A number of studies have examined cytokine and chemokines in SSPE brain or animal model systems. IFNγ and TNF alpha (TNFα) were found to be expressed in endothelial and glial cells (Anlar et al., 2001). Furthermore, MV has recently been shown to up-regulate the virus receptor polio-like receptor-4 (PVRL4, also known as nectin-4) in human brain endothelial cells and cause apoptosis by induction of TRAIL (Abdullah et al., 2013). The inflammatory lesions in SSPE consist of various cell subtypes and cytokines localized in particular regions of the brain, and these show certain associations with clinical course. Using in situ hybridization, IL2, IL6, TNF and leukaemia inhibitory factor (LIF) mRNA have been demonstrated in cells in the inflammatory infiltrate as well as in glial cells in foci of infection in cases of SSPE. LIF mRNA was also present in neurons in these areas. In the same study, LIF was also produced after MV infection in a human neuronal cell line (McQuaid et al., 1997). In contrast, the type-I IFN inducible human MxA protein, which exhibits antiviral activity against a number of RNA viruses, including MV, was reported to be highly expressed in the area surrounding, but not in the centre of, MV-antigen-positive lesions in SSPE brains. This pattern of MxA expression indicates that newly infected cells release type I IFN and are demarcated by a protecting barrier of MxA-expressing cells. Expression of MxA was found mainly in the cytoplasm of astrocytes and did not correlate with the presence of infiltrates of inflammatory cells, although some lymphoid cells were positive for MxA (Ogata et al., 2004). Proinflammatory chemokines were found to be produced in a transgenic mouse model of neuron-restricted MV infection as well as in neurons derived from these mice. The chemokines were IFNγ inducible protein (IP10), C–X–C motif chemokine-10 (CXCL10), monokine inducible by IFNγ (Mig), CXCL9 and RANTES (CCL5) (Patterson et al., 2003). Overall, the above studies indicate that neurons as well as glia play important roles in the protective antiviral response to MV in the CNS.

The pattern of inflammatory cell infiltration has been studied in the frontal brain biopsies of 28 cases of SSPE by immunohistochemistry. Lymphocytic infiltration and gliosis were common pathologic findings. CD4⁺ T cells were observed in perivascular areas, and CD8⁺ lymphocytes in the brain parenchyma. B cells were located in large perivascular cuffs associated with a longer and slower disease course (Anlar et al., 2004). The T cell response in SSPE was also investigated by examining proliferation and cytokine secretion of cells from 35 patients and 42 healthy controls in response to virus and a number of CNS antigens. Proliferation in response to myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG) and the heat shock protein alpha B-crystallin (HSPB5) did not differ between the groups. IL12 secretion of peripheral blood leukocytes from SSPE patients to MV antigen was lower than in controls, and IFNγ, IL12 and IL10 production was also impaired in SSPE patients. The results did not demonstrate any bystander cellular response against myelin antigens, indicating that the CNS is not a predominant target of an autoimmune response in SSPE (Yentür et al., 2005) unlike post-infection encephalitis.

A number of studies have been carried out to investigate MV clearance from the CNS. Investigation of humans with genetic or acquired deficiencies of either the humoral or cellular arm of the immune system, and rodent models, have implicated T cells in the control of ongoing MV infection. Using a transgenic mouse model in conjunction with depletion and reconstitution of individual B and T cell subsets alone or in combination, it was shown that neither CD4⁺–CD8⁺ T cells nor B cells alone are responsible for virus clearance. However, combinations of either CD4⁺ T cells or B cells, or of CD4⁺ and CD8⁺ T cells, are essential but CD8⁺ T cells with B cells are ineffective in control of virus levels. IFNγ and neutralizing antibodies to MV, but not perforin or TNFα alone, are associated with clearance of infection. TNFα combined with IFNγ is more effective in protection than IFNγ alone (Tishon et al., 2006). A more recent study has shown that primed T cells directly act to clear MV infection in the CNS by using a non-cytolytic IL12 and IFNγ-dependent mechanism and that this mechanism relies upon Janus kinase (Jak)–STAT signalling (Stubblefield-Park et al., 2011). Therefore, lack of an appropriate IFNγ response is likely to be a major factor in establishment of persistence of MV in the CNS. Current treatment for SSPE may slow the disease to some extent and comprises IFNα, ribavirin and inosiplex, either separately or in combination (Solomon et al., 2002). However, clearance when the virus is in a long-term persistent state is unlikely to occur.

The role of regulatory T cells (Tregs) as regulators of the immune response in the brain in MV infection has recently been investigated (Reuter et al., 2012). It was found that persistent CNS infection in mice can be modulated by manipulation of Tregs in the periphery. CD4⁺ CD25⁺ Foxp3⁺ Tregs were expanded or depleted during the persistent phase of the CNS infection, and the virus-specific immune response and level of virus replication were analysed. Expansion of Tregs increased virus replication and spread in the brain. In contrast, depletion of Tregs induced an increase of virus-specific CD8⁺ effector T cells in the CNS and caused a reduction of infection.

The Bunyaviridae family contains more than 258 viruses and is divided into five genera, four of which comprise animal viruses some of which present serious risks to humans. The family includes Phleboviruses (e.g. Rift Valley fever (RVFV)), Nairovirus (e.g. Crimean–Congo haemorrhagic fever (CHFV)), Bunyavirus and Hantaviruses including some of the haemorrhagic fevers (Charrel et al., 2004). Toscana virus is a newly emerging virus transmitted by phlebotomus sandflies and initially discovered in central Italy, but it has also now been found in other European countries. Hantaviruses (e.g. Hantaan virus) are another, emerging group of viruses causing epidemics in the United States. Bunyavirus is the largest genus (Calisher, 1994), and symptoms caused by members include fever, rash, arthritis, encephalitis and hepatitis. These infections are common in Africa and South America. In the United States, only the California group of viruses are present, one of which is the La Crosse virus. Clinical features of this infection range from a mild febrile illness to aseptic meningitis and fatal encephalitis. Most children with symptomatic disease have signs of encephalitis, with nearly one-half having seizures (Rust et al., 1999).