JC Polyomavirus, progressive multifocal leukoencephalopathy and immune reconstitution inflammatory syndrome: a review.

The human neurotropic virus JC Polyomavirus, a member of the Polyomaviridae family, is the opportunistic infectious agent causing progressive multifocal leukoencephalopathy, typically in immunocompromised individuals. The spectrum of underlying reasons for the systemic immunosuppression that permits JCV infection in the central nervous system has evolved over the past 2 decades, and therapeutic immunosuppression arousing JCV infection in the brain has become increasingly prominent as a trigger for PML. Effective immune restoration subsequent to human immunodeficiency virus-related suppression is now recognized as a cause for unexpected deterioration of symptoms in patients with PML, secondary to a rebound inflammatory phenomenon called immune reconstitution inflammatory syndrome, resulting in significantly increased morbidity and mortality in a disease already infamous for its lethality. This review addresses current knowledge regarding JC Polyomavirus, progressive multifocal leukoencephalopathy, progressive multifocal leukoencephalopathy-related immune reconstitution inflammatory syndrome, and the immunocompromised states that incite JC Polyomavirus central nervous system infection, and discusses prospects for the future management of these conditions.

A survey of known immune epitopes in the enteroviruses strains associated with acute flaccid myelitis.

Enteroviruses are potentially linked to the emergence of Acute Flaccid Myelitis (AFM), a rare but very serious condition that affects the nervous system. AFM has been associated with coxsackievirus A16, enterovirus A71 (EVA71) and enterovirus D68 (EVD68). Little is known about host-pathogen interactions for these viruses, and whether immune responses may have a protective or immunopathological role in disease presentations. Towards addressing this issue, we used the Immune Epitope Database to assess the known inventory of B and T cell epitopes from enteroviruses, focusing on data related to human hosts. The extent of conservation in areas that are targets of B and T cell immune responses were examined. This analysis sheds light on regions of the enterovirus polypeptide that can be probed to induce a specific or cross-reactive B or T cell the immune response to enteroviruses, with a particular focus on coxsackievirus A16, EVA71 and EVD68. In addition, these analyses reveal the current gap-of-knowledge in the T and B cell immune responses that future studies should aim to address.

Chronic Viral Neuroinflammation: Speculation on Underlying Mechanisms.

Viral infection in the brain can be acute or chronic, with the responses often producing foci of increasingly cytotoxic inflammation. This can lead to effects beyond the central nervous system (CNS). To stimulate discussion, this commentary addresses four questions: What drives the development of human immunodeficiency virus (HIV)-associated neurocognitive disorders, does the phenotype of macrophages in the CNS spur development of HIV encephalitis (HIVE), does continual activation of astrocytes drive the development of HIV-associated neurocognitive disorders/subclinical disease, and neuroinflammation: friend or foe? A unifying theory that connects each question is the issue of continued activation of glial cells, even in the apparent absence of simian immunodeficiency virus/HIV in the CNS. As the CNS innate immune system is distinct from the rest of the body, it is likely there could be a number of activation profiles not observed elsewhere.

B-cell posttransplant lymphoproliferative disorder isolated to the central nervous system is Epstein-Barr virus positive and lacks p53 and Myc expression by immunohistochemistry.

In this retrospective study from one institution, we performed a clinicopathological study of a cohort of patients with posttransplant lymphoproliferative disorder (PTLD) confined to the central nervous system. We also identified a comparison cohort of patients with de novo primary diffuse large B-cell lymphoma of the central nervous system. We performed a detailed morphologic review, evaluated Epstein-Barr virus (EBV) by in situ hybridization, and interpreted a panel of immunohistochemical stains in a subset of cases including Hans classification markers (CD10, BCL6, MUM1), p53, CD30, Myc, and BCL2. All 17 of the posttransplant and none of 11 de novo cases were EBV positive (P < .005). Morphologic patterns identified in the PTLD cases were monomorphic diffuse large B-cell lymphoma pattern (10 patients) and "T-cell-rich" pattern (7 patients). The monomorphic posttransplant cases were more likely to be Myc negative (P = .015) and CD30 positive (P < .005) than the de novo cases, and showed a similarly low rate of p53 positivity by immunohistochemistry. No prognostic factors for overall survival were identified. Central nervous system PTLD is EBV positive, typically lacks p53 and Myc expression by immunohistochemistry, and can present with numerous background T lymphocytes.

SAMHD1 transcript upregulation during SIV infection of the central nervous system does not associate with reduced viral load.

Restriction of HIV-1 in myeloid-lineage cells is attributed in part to the nucleotidase activity of the SAM-domain and HD-domain containing protein (SAMHD1), which depletes free nucleotides, blocking reverse transcription. In the same cells, the Vpx protein of HIV-2 and most SIVs counteracts SAMHD1. Both Type I and II interferons may stimulate SAMHD1 transcription. The contributions of SAMHD1 to retroviral restriction in the central nervous system (CNS) have been the subject of limited study. We hypothesized that SAMHD1 would respond to interferon in the SIV-infected CNS but would not control virus due to SIV Vpx. Accordingly, we investigated SAMHD1 transcript abundance and association with the Type I interferon response in an SIV model. SAMHD1 transcript levels were IFN responsive, increasing during acute phase infection and decreasing during a more quiescent phase, but generally remaining elevated at all post-infection time points. In vitro, SAMHD1 transcript was abundant in macaque astrocytes and further induced by Type I interferon, while IFN produced a weaker response in the more permissive environment of the macrophage. We cannot rule out a contribution of SAMHD1 to retroviral restriction in relatively non-permissive CNS cell types. We encourage additional research in this area, particularly in the context of HIV-1 infection.

Coronavirus Infections in the Central Nervous System and Respiratory Tract Show Distinct Features in Hospitalized Children.

BACKGROUND/AIMS: Coronavirus (CoV) infections induce respiratory tract illnesses and central nervous system (CNS) diseases. We aimed to explore the cytokine expression profiles in hospitalized children with CoV-CNS and CoV-respiratory tract infections. METHODS: A total of 183 and 236 hospitalized children with acute encephalitis-like syndrome and respiratory tract infection, respectively, were screened for anti-CoV IgM antibodies. The expression profiles of multiple cytokines were determined in CoV-positive patients. RESULTS: Anti-CoV IgM antibodies were detected in 22/183 (12.02%) and 26/236 (11.02%) patients with acute encephalitis-like syndrome and respiratory tract infection, respectively. Cytokine analysis revealed that the level of serum granulocyte colony-stimulating factor (G-CSF) was significantly higher in both CoV-CNS and CoV-respiratory tract infection compared with healthy controls. Additionally, the serum level of granulocyte macrophage colony-stimulating factor (GM-CSF) was significantly higher in CoV-CNS infection than in CoV-respiratory tract infection. In patients with CoV-CNS infection, the levels of IL-6, IL-8, MCP-1, and GM-CSF were significantly higher in their cerebrospinal fluid samples than in matched serum samples. CONCLUSION: To the best of our knowledge, this is the first report showing a high incidence of CoV infection in hospitalized children, especially with CNS illness. The characteristic cytokine expression profiles in CoV infection indicate the importance of host immune response in disease progression.

Divergent cerebrospinal fluid cytokine network induced by non-viral and different viral infections on the central nervous system.

BACKGROUND: Meningoencephalitis is one of the most common disorders of the central nervous system (CNS) worldwide. Viral meningoencephalitis differs from bacterial meningitis in several aspects. In some developing countries, bacterial meningitis has appropriate clinical management and chemotherapy is available. Virus-associated and virus not detected meningoencephalitis are treatable, however, they may cause death in a few cases. The knowledge of how mediators of inflammation can induce disease would contribute for the design of affordable therapeutic strategies, as well as to the diagnosis of virus not detected and viral meningoencephalitis. Cytokine-induced inflammation to CNS requires several factors that are not fully understood yet. METHODS: Considering this, several cytokines were measured in the cerebrospinal fluid (CSF) of patients with undiagnosed and viral meningoencephalitis, and these were correlated with cellularity in the CSF. RESULTS: The results demonstrate that an altered biochemical profile alongside increased cellularity in the cerebrospinal fluid is a feature of patients with meningoencephalitis that are not associated with the detection of virus in the CNS (P < 0.05). Moreover, HIV-positive patients (n = 10) that evolve with meningoencephalitis display a distinct biochemical/cytological profile (P < 0.05) in the cerebrospinal fluid. Meningoencephalitis brings about a prominent intrathecal cytokine storm regardless of the detection of virus as presumable etiological agent. In the case of Enterovirus infection (n = 13), meningoencephalitis elicits robust intrathecal pro-inflammatory cytokine pattern and elevated cellularity when compared to herpesvirus (n = 15) and Arbovirus (n = 5) viral infections (P < 0.05). CONCLUSION: Differences in the cytokine profile of the CSF may be unique if distinct, viral or presumably non-viral pathways initially trigger the inflammatory response in the CNS.

Transcriptional Regulation of CXCL5 in HIV-1-Infected Macrophages and Its Functional Consequences on CNS Pathology.

Human immunodeficiency virus-1 (HIV-1)-infected monocytes/macrophages and microglia release increased levels of proinflammatory cytokines and chemokines, including ELR+ (containing glutamic acid-leucine-arginine motif) chemokines. To investigate the role of HIV-1 infection on chemokine regulation, monocyte-derived macrophages (MDMs) from normal donors were infected with HIV-1 and the expression of chemokines and their downstream biological functions were evaluated. Among the tested chemokines, CXCL5 was upregulated significantly both at the mRNA and protein level in the HIV-1-infected MDMs compared with mock-infected cultures. Upregulation of CXCL5 in the HIV-1-infected MDMs is, in part, regulated by increased interleukin-1ß (IL-1ß) production and phosphorylation of ERK1/2. Functional analyses indicate that HIV-1-induced overexpression of CXCL5 has enhanced the ability to attract neutrophils, as observed by chemotaxis assay. However, exposure of NT2, SH-SY5Y cells, and primary neurons to HIV-1-infected MDM supernatants resulted in cell death that was not rescued by anti-CXCL5 antibody suggesting that CXCL5 does not have direct effect on neuronal death. Together, these results suggest that the increased level of CXCL5 in tissue compartments, including the central nervous system of HIV-1-infected individuals might alter the inflammatory response through the infiltration of neutrophils into tissue compartment, thus causing secondary effects on resident cells.

Hantaviruses induce antiviral and pro-inflammatory innate immune responses in astrocytic cells and the brain.

Although hantaviruses are not generally considered neurotropic, neurological complications have been reported occasionally in patients with hemorrhagic fever renal syndrome (HFRS). In this study, we analyzed innate immune responses to hantavirus infection in vitro in human astrocytic cells (A172) and in vivo in suckling ICR mice. Infection of A172 cells with pathogenic Hantaan virus (HTNV) or a novel shrew-borne hantavirus, known as Imjin virus (MJNV), induced activation of antiviral genes and pro-inflammatory cytokines/chemokines. MicroRNA expression profiles of HTNV- and MJNV-infected A172 cells showed distinct changes in a set of miRNAs. Following intraperitoneal inoculation with HTNV or MJNV, suckling ICR mice developed rapidly progressive, fatal central nervous system-associated disease. Immunohistochemical staining of virus-infected mouse brains confirmed the detection of viral antigens within astrocytes. Taken together, these findings suggest that the neurological findings in HFRS patients may be associated with hantavirus-directed modulation of innate immune responses in the brain.

SARM is required for neuronal injury and cytokine production in response to central nervous system viral infection.

Four of the five members of the Toll/IL-1R domain-containing adaptor family are required for signaling downstream of TLRs, promoting innate immune responses against different pathogens. However, the role of the fifth member of this family, sterile α and Toll/IL-1R domain-containing 1 (SARM), is unclear. SARM is expressed primarily in the CNS where it is required for axonal death. Studies in Caenorhabditis elegans have also shown a role for SARM in innate immunity. To clarify the role of mammalian SARM in innate immunity, we infected SARM(-/-) mice with a number of bacterial and viral pathogens. SARM(-/-) mice show normal responses to Listeria monocytogenes, Mycobacterium tuberculosis, and influenza virus, but show dramatic protection from death after CNS infection with vesicular stomatitis virus. Protection correlates with reduced CNS injury and cytokine production by nonhematopoietic cells, suggesting that SARM is a positive regulator of cytokine production. Neurons and microglia are the predominant source of cytokines in vivo, supporting a role for SARM as a link between neuronal injury and innate immunity.

Pathogenesis of murine coronavirus in the central nervous system.

Murine coronavirus (mouse hepatitis virus, MHV) is a collection of strains that induce disease in several organ systems of mice. Infection with neurotropic strains JHM and A59 causes acute encephalitis, and in survivors, chronic demyelination, the latter of which serves as an animal model for multiple sclerosis. The MHV receptor is a carcinoembryonic antigen-related cell adhesion molecule, CEACAM1a; paradoxically, CEACAM1a is poorly expressed in the central nervous system (CNS), leading to speculation of an additional receptor. Comparison of highly neurovirulent JHM isolates with less virulent variants and the weakly neurovirulent A59 strain, combined with the use of reverse genetics, has allowed mapping of pathogenic properties to individual viral genes. The spike protein, responsible for viral entry, is a major determinant of tropism and virulence. Other viral proteins, both structural and nonstructural, also contribute to pathogenesis in the CNS. Studies of host responses to MHV indicate that both innate and adaptive responses are crucial to antiviral defense. Type I interferon is essential to prevent very early mortality after infection. CD8 T cells, with the help of CD4 T cells, are crucial for viral clearance during acute disease and persist in the CNS during chronic disease. B cells are necessary to prevent reactivation of virus in the CNS following clearance of acute infection. Despite advances in understanding of coronavirus pathogenesis, questions remain regarding the mechanisms of viral entry and spread in cell types expressing low levels of receptor, as well as the unique interplay between virus and the host immune system during acute and chronic disease.

Emerging viral infections of the central nervous system: part 2.

The first part of this review ended with a discussion of new niches for known viruses as illustrated by viral central nervous system (CNS) disease associated with organ transplant and the syndrome of human herpesvirus 6-associated posttransplant acute limbic encephalitis. In this part, we begin with a continuation of this theme, reviewing the association of JC virus-associated progressive multifocal leukoencephalopathy (PML) with novel immunomodulatory agents. This part then continues with emerging viral infections associated with importation of infected animals (monkeypox virus), then spread of vectors and enhanced vector competence (chikungunya virus [CHIK]), and novel viruses causing CNS infections including Nipah and Hendra viruses and bat lyssaviruses (BLV).

CNS inflammation and macrophage/microglial biology associated with HIV-1 infection.

Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system (CNS) can result in neurological dysfunction with devastating consequences in a significant proportion of individuals with acquired immune deficiency syndrome. HIV-1 does not infect neurons directly but induces damage indirectly through the accumulation of activated macrophage/microglia (M/M) cells, some of which are infected, that release neurotoxic mediators including both cellular activation products and viral proteins. One mechanism for the accumulation of activated M/M involves the development in infected individuals of an activated peripheral blood monocyte population that traffics through the blood-brain barrier, a process that also serves to carry virus into CNS and establish local infection. A second mechanism involves the release by infected and activated M/M in the CNS of chemotactic mediators that recruit additional monocytes from the periphery. These activated M/M, some of which are infected, release a number of cytokines and small molecule mediators as well as viral proteins that act on bystander cells and in turn activate them, thus amplifying the cascade. These viral proteins and cellular products have neurotoxic properties as well, both directly and through induction of astrocyte dysfunction, which ultimately lead to neuronal injury and death. In patients effectively treated with antiretroviral therapy, frank dementia is now uncommon and has been replaced by milder forms of neurocognitive impairment, with less frequent and more focal neuropathology. This review summarizes key findings that support the critical role and mechanisms of monocyte/macrophage activation and inflammation as a major component for HIV-1 encephalitis or HIV-1 associated dementia.

Peripheral challenge with double-stranded RNA elicits global up-regulation of cytokine gene expression in the brain.

It is well established that mediators of peripheral inflammation are relayed to the brain and elicit sickness behavior via neuroinflammatory agents that target neuronal substrates. In the present study, we used double-stranded RNA (dsRNA), a viral replication intermediate, to mimic the acute phase of viral infection. C57BL/6 mice were injected intraperitoneally with 12 mg/kg of synthetic dsRNA, i.e., polyinosinic-polycytidylic acid (PIC). The treatment induced severe sickness behavior in the animals as revealed by the burrowing test performed 6 hr postinjection. PIC challenge also induced up-regulation of mRNA for several cytokines in the brain as determined by real-time quantitative RT-PCR. In all brain regions, i.e., the forebrain, brainstem, and cerebellum, the gene encoding the CXCL2 chemokine featured the most robust up-regulation over the basal level (saline-injected animals), followed by the genes encoding the CCL2 chemokine, interferon-beta (IFNbeta), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFalpha), and interleukin-1beta (IL-1beta). The forebrain featured the highest extent of up-regulation of the Ifnb gene, whereas the other genes attained the highest expression in the cerebellum. Most of the genes featured transient up-regulation, with peaks occurring 3-6 hr after PIC challenge. The TNFalpha, CCL2, CXCL2, IFNbeta, and IL-1beta messages remained profoundly up-regulated even at 24 hr. The expression of genes encoding inducible and neuronal nitric oxide synthase (NOS) in the brain was not affected by the peripheral PIC challenge. However, the endothelial NOS message was initially down-regulated and subsequently up-regulated, indicating stimulation of cerebral vasculature.

IL-15 independent maintenance of virus-specific CD8(+) T cells in the CNS during chronic infection.

The role of IL-15 in T cell survival was examined during chronic CNS coronavirus infection. Similar numbers of virus-specific CD8(+) T cells were retained in the CNS of IL-15(-/-) and wt mice, consistent with loss of IL-2/15 receptor (CD122) expression. IL-15 deficiency also had no affect on IL-7 receptor (CD127) expression, Bcl-2 upregulation, granzyme B expression, or IFN-gamma secretion in CNS persisting CD8(+) T cells. Furthermore, CD8(+) T cell division in the CNS was reduced compared to spleen. CD8(+) T cells in the persistently infected CNS are thus characterized by IL-15 independent, low level proliferation and an activated/memory phenotype.

Role of IFN-gamma responsiveness in CD8 T-cell-mediated viral clearance and demyelination in coronavirus-infected mice.

Immunocompetent, but not RAG1(-/-) mice infected with MHV-JHM develop demyelination. Transferred CD8 T cell-enriched splenocytes reconstitute demyelination, and this ability is dependent on donor IFN-gamma. We used IFN-gammaR1(-/-) mice to examine the target of IFN-gamma in CD8 T cell-mediated demyelination. In IFN-gammaR1(-/-)RAG1(-/-) recipients, demyelination is decreased, but not eliminated, while viral titers are significantly increased when compared to IFN-gammaR1(+/+)RAG1(-/-) recipients. IFN-gammaR1(-/-) CD8 T cells retain virus-specific effector function regardless of IFN-gammaR1 expression. Although IFN-gammaR1 responsiveness is critical for maximal demyelination, increased levels of infectious virus coupled with adoptive transfer of CD8 T cells may result in myelin destruction independent of IFN-gammaR1 expression.

Increased proinflammatory cytokine and chemokine responses and microglial infection following inoculation with neural stem cells infected with polytropic murine retroviruses.

Proinflammatory cytokines and chemokines are often detected in brain tissue of patients with neurological diseases such as multiple sclerosis (MS), HIV-associated dementia (HAD) and Alzheimer's disease (AD). We have utilized a mouse model of retrovirus-induced neurological disease to examine how these proinflammatory responses contribute to neuropathogenesis. In previous studies with this model, a correlation was found between neurovirulence and cytokine and chemokine expression. However, it was unclear whether the induction of these cytokines and chemokines was in response to specific virus envelope determinants or was regulated by the level of virus infection in the brain. In the current study, we demonstrated that multiple polytropic retroviruses induced cytokine and chemokine mRNA expression following increased virus levels in the brain. Increased virus levels of polytropic viruses also correlated with increased neuropathogenesis. In contrast, the ecotropic retrovirus, FB29, did not induce cytokine or chemokine mRNA expression or neurological disease, despite virus levels either similar to or higher than the polytropic retroviruses. As polytropic and ecotropic viruses utilize different receptors for entry, these receptors may play a critical role in the induction of these innate immune responses in the brain.

Altered immune response to CNS viral infection in mice with a conditional knock-down of macrophage-lineage cells.

Neuroadapted Sindbis Virus (NSV) is a neuronotropic virus that causes hindlimb paralysis in susceptible mice and rats. The authors and others have demonstrated that though death of infected motor neurons occurs, bystander death of uninfected neurons also occurs and both contribute to the paralysis that ensues following infection. The authors have previously shown that the treatment of NSV-infected mice with minocycline, an inhibitor that has many functions within the central nervous system (CNS), including inhibiting microglial activation, protects mice from paralysis and death. The authors, therefore, proposed that microglial activation may contribute to bystander death of motor neurons following NSV infection. Here, the authors tested the hypothesis using a conditional knock-out of activated macrophage-lineage cells, including endogenous CNS macrophage cells. Surprisingly, ablation of these cells resulted in more rapid death and similar weakness in the hind limbs of NSV-infected animals compared with that of control animals. Several key chemokines including IL-12 and monocyte chemoattractant protein-1 (MCP-1) did not become elevated in these animals, resulting in decreased infiltration of T lymphocytes into the CNS of the knock-down animals. Either because of the decreased macrophage activation directly or because of the reduced immune cell influx, viral replication persisted longer within the nervous system in knock-down mice than in wild type mice. The authors, therefore, conclude that although macrophage-lineage cells in the CNS may contribute to neurodegeneration in certain situations, they also serve a protective role, such as control of viral replication.

Immunophenotypic patterns of T-cell activation in neuroinflammatory diseases.

OBJECTIVES: We aimed to gain insights into the pathogen-specific differences in early adaptive immune responses following central nervous system infections with Borrelia burgdorferi and viral pathogens by studying the immunophenotypic patterns of T-cell activation. Moreover, we wished to determine whether the expression of T-cell activation markers reflects disease activity in multiple sclerosis (MS). METHODS: Proportions of cerebrospinal fluid T-cells expressing the markers HLA-DR, CD25 and CD38 were determined in patients with MS (n = 40), acute viral meningomyeloradiculoneuritis (VID, n = 26), early neuroborreliosis (NB, n = 23) and non-inflammatory neurologic diseases (n = 51) by using flow cytometry. In relapsing-remitting MS, disease activity was assessed by clinical examination and magnetic resonance imaging. RESULTS: For each of the surface markers that were examined, significant differences in T cell proportions were found between patient groups. The proportion of HLA-DR+ T cells was higher and that of CD25+ T cells lower in NB compared with VID. These differences were attributable only to the early phase of the disease (< or = 6 days after symptom onset). Among MS patients, there was a trend for higher proportions of T cells expressing activation markers in patients with gadolinium-enhancing lesions. CONCLUSIONS: The decreased CD25 expression in NB may reflect immunomodulatory effects of B. burgdorferi facilitating persistent infection. Larger prospective studies of T-cell activation markers for ascertaining the association between cellular markers and clinical surrogates of disease activity in MS are warranted.