Neurological complications associated with emerging viruses in Brazil.

OBJECTIVE: To test the hypotheses that emerging viruses are associated with neurological hospitalizations and that statistical models can be used to predict neurological sequelae from viral infections. METHODS: An ecological study was carried out to observe time trends in the number of hospitalizations with inflammatory polyneuropathy and Guillain-Barré syndrome (GBS) in the state of Rio de Janeiro from 1997 to 2017. Increases in GBS from month to month were assessed using a Farrington test. In addition, a cross-sectional study was conducted analyzing 50 adults hospitalized for inflammatory polyneuropathies from 2015 to 2017. The extent to which Zika virus symptoms explained GBS hospitalizations was evaluated using a calibration test. RESULTS: There were significant increases (Farrington test, P<0.001) in the incidence of GBS following the introduction of influenza A/H1N1 in 2009, dengue virus type 4 in 2013, and Zika virus in 2015. Of 50 patients hospitalized, 14 (28.0%) were diagnosed with arboviruses, 9 (18.0%) with other viruses, and the remainder with other causes of such neuropathies. Statistical models based on cases of emerging viruses accurately predicted neurological sequelae, such as GBS. CONCLUSION: The introduction of novel viruses increases the incidence of inflammatory neuropathies.

Autoimmune neuroretinopathy secondary to Zika virus infection. / Neurorretinopatía autoinmune secundaria a infección por el virus del Zika.

CASE REPORT: A 40-year-old woman diagnosed with Zika virus infection 6 months before she arrived at this hospital. She referred to a progressive and painless vision loss, of 2 weeks onset after the infection diagnosis. She was treated with topical steroids. Previous visual acuity was recovered, but she still refers to reduced visual field and nyctalopia. Ophthalmologic examination revealed severe retinal sequels, compatible with autoimmune retinopathy. Based on the clinical features and the temporal relationship with Zika virus infection, non-para-neoplastic autoimmune retinopathy was diagnosed and managed with steroids and infliximab. DISCUSSION: Zika virus can trigger a non-para-neoplastic autoimmune retinopathy. The diagnosis is based on clinical features, and requires early immunosuppressive therapy.

A SAMHD1 mutation associated with Aicardi-Goutières syndrome uncouples the ability of SAMHD1 to restrict HIV-1 from its ability to downmodulate type I interferon in humans.

Mutations in the human SAMHD1 gene are known to correlate with the development of the Aicardi-Goutières syndrome (AGS), which is an inflammatory encephalopathy that exhibits neurological dysfunction characterized by increased production of type I interferon (IFN); this evidence has led to the concept that the SAMHD1 protein negatively regulates the type I IFN response. Additionally, the SAMHD1 protein has been shown to prevent efficient HIV-1 infection of macrophages, dendritic cells, and resting CD4+ T cells. To gain insights on the SAMHD1 molecular determinants that are responsible for the deregulated production of type I IFN, we explored the biochemical, cellular, and antiviral properties of human SAMHD1 mutants known to correlate with the development of AGS. Most of the studied SAMHD1 AGS mutants exhibit defects in the ability to oligomerize, decrease the levels of cellular deoxynucleotide triphosphates in human cells, localize exclusively to the nucleus, and restrict HIV-1 infection. At least half of the tested variants preserved the ability to be degraded by the lentiviral protein Vpx, and all of them interacted with RNA. Our investigations revealed that the SAMHD1 AGS variant p.G209S preserve all tested biochemical, cellular, and antiviral properties, suggesting that this residue is a determinant for the ability of SAMHD1 to negatively regulate the type I IFN response in human patients with AGS. Overall, our work genetically separated the ability of SAMHD1 to negatively regulate the type I IFN response from its ability to restrict HIV-1.

Narcolepsy as an autoimmune disease: the role of H1N1 infection and vaccination.

Narcolepsy is a sleep disorder characterised by loss of hypothalamic hypocretin (orexin) neurons. The prevalence of narcolepsy is about 30 per 100 000 people, and typical age at onset is 12-16 years. Narcolepsy is strongly associated with the HLA-DQB1*06:02 genotype, and has been thought of as an immune-mediated disease. Other risk genes, such as T-cell-receptor α chain and purinergic receptor subtype 2Y11, are also implicated. Interest in narcolepsy has increased since the epidemiological observations that H1N1 infection and vaccination are potential triggering factors, and an increase in the incidence of narcolepsy after the pandemic AS03 adjuvanted H1N1 vaccination in 2010 from Sweden and Finland supports the immune-mediated pathogenesis. Epidemiological observations from studies in China also suggest a role for H1N1 virus infections as a trigger for narcolepsy. Although the pathological mechanisms are unknown, an H1N1 virus-derived antigen might be the trigger.

SAMHD1 restricts HIV-1 infection in resting CD4(+) T cells.

Unlike activated CD4(+) T cells, resting CD4(+) T cells are highly resistant to productive HIV-1 infection. Early after HIV-1 entry, a major block limits reverse transcription of incoming viral genomes. Here we show that the deoxynucleoside triphosphate triphosphohydrolase SAMHD1 prevents reverse transcription of HIV-1 RNA in resting CD4(+) T cells. SAMHD1 is abundantly expressed in resting CD4(+) T cells circulating in peripheral blood and residing in lymphoid organs. The early restriction to infection in unstimulated CD4(+) T cells is overcome by HIV-1 or HIV-2 virions into which viral Vpx is artificially or naturally packaged, respectively, or by addition of exogenous deoxynucleosides. Vpx-mediated proteasomal degradation of SAMHD1 and elevation of intracellular deoxynucleotide pools precede successful infection by Vpx-carrying HIV. Resting CD4(+) T cells from healthy donors following SAMHD1 silencing or from a patient with Aicardi-Goutières syndrome homozygous for a nonsense mutation in SAMHD1 were permissive for HIV-1 infection. Thus, SAMHD1 imposes an effective restriction to HIV-1 infection in the large pool of noncycling CD4(+) T cells in vivo. Bypassing SAMHD1 was insufficient for the release of viral progeny, implicating other barriers at later stages of HIV replication. Together, these findings may unveil new ways to interfere with the immune evasion and T cell immunopathology of pandemic HIV-1.

SAMHD1-deficient CD14+ cells from individuals with Aicardi-Goutières syndrome are highly susceptible to HIV-1 infection.

Myeloid blood cells are largely resistant to infection with human immunodeficiency virus type 1 (HIV-1). Recently, it was reported that Vpx from HIV-2/SIVsm facilitates infection of these cells by counteracting the host restriction factor SAMHD1. Here, we independently confirmed that Vpx interacts with SAMHD1 and targets it for ubiquitin-mediated degradation. We found that Vpx-mediated SAMHD1 degradation rendered primary monocytes highly susceptible to HIV-1 infection; Vpx with a T17A mutation, defective for SAMHD1 binding and degradation, did not show this activity. Several single nucleotide polymorphisms in the SAMHD1 gene have been associated with Aicardi-Goutières syndrome (AGS), a very rare and severe autoimmune disease. Primary peripheral blood mononuclear cells (PBMC) from AGS patients homozygous for a nonsense mutation in SAMHD1 (R164X) lacked endogenous SAMHD1 expression and support HIV-1 replication in the absence of exogenous activation. Our results indicate that within PBMC from AGS patients, CD14+ cells were the subpopulation susceptible to HIV-1 infection, whereas cells from healthy donors did not support infection. The monocytic lineage of the infected SAMHD1 -/- cells, in conjunction with mostly undetectable levels of cytokines, chemokines and type I interferon measured prior to infection, indicate that aberrant cellular activation is not the cause for the observed phenotype. Taken together, we propose that SAMHD1 protects primary CD14+ monocytes from HIV-1 infection confirming SAMHD1 as a potent lentiviral restriction factor.

Restricted access to myeloid cells explained.

The lentiviral accessory protein, Vpx, is known to counteract a restriction factor that is specific to myeloid cells, such as macrophages and dendritic cells. This review summarizes the findings in two seminal studies that identify SAMHD1 as the cellular protein that is responsible for myeloid cell restriction, and establish the existence of other types of restriction in these cells.

Herpes simplex type I (HSV-1) infection of the nervous system: is an immune response a good thing?

Herpes simplex virus type 1 (HSV-1) can induce a robust immune response initially thru the activation of pattern recognition receptors and subsequent type I interferon production that then shapes, along with other innate immune components, the adaptive immune response to the insult. While this response is necessary to quell virus replication, drive the pathogen into a "latent" state, and likely hinder viral reactivation, collateral damage can ensue with demonstrable cell death and foci of tissue pathology in the central nervous system (CNS) as a result of the release of inflammatory mediators including reactive oxygen species. Although rare, HSV-1 is the leading cause of frank sporadic encephalitis that, if left untreated, can result in death. A greater understanding of the contribution of resident glial cells and infiltrating leukocytes within the CNS in response to HSV-1 invasion is necessary to identify candidate molecules as targets for therapeutic intervention to reduce unwarranted inflammation coinciding with the maintenance of the anti-viral state.

Sequential polymicrobial infections lead to CNS inflammatory disease: possible involvement of bystander activation in heterologous immunity.

VV(PLP) is a recombinant vaccinia virus (VV) encoding myelin proteolipid protein (PLP) that has been used to investigate molecular mimicry and autoimmunity. Since virus infections can cause bystander activation, mice were first infected with VV(PLP), and later challenged with wild-type VV, lymphocytic choriomeningitis virus (LCMV), or murine cytomegalovirus (MCMV). Among the VV(PLP)-primed mice, only MCMV challenge induced significant Ki-67(+), CD3(+)T cell infiltration into the central nervous system (CNS) with a mild PLP antibody response. While MCMV alone caused no CNS disease, control VV-infected mice followed with MCMV developed mild CNS inflammation. Thus, heterologous virus infections can induce CNS pathology.

Immune reconstitution syndrome presenting with cerebral varicella zoster vasculitis in HIV-1-infected patient: a case report.

Neurologic dysfunction complicating HIV infection may occur in up to 70% of AIDS patients. The advent of highly active antiretroviral therapy has reduced central nervous system opportunistic infections. Immune reconstitutions after highly active antiretroviral therapy also lead to atypical presentations of neurologic opportunistic infections. We report a man who developed an encephalitic illness 10 months after institution of highly active antiretroviral therapy and improvement in his CD4 count. Varicella zoster vasculitis involving the brain was suspected. Acyclovir therapy resulted in complete clinical and radiologic recovery. Symptomatic reactivation of varicella zoster infection within the encephalon during therapeutic immunologic reconstitution is rare and should be suspected, especially in patients with neurologic syndrome consistent with encephalitis with recent history of herpes zoster and multiple, discrete areas of infarct or demyelination on brain magnetic resonance imaging. The clinical and neuroradiologic features of this condition and its relevance to the immune reconstitution syndrome are discussed.

Immune reconstitution inflammatory syndrome in the CNS of HIV-infected patients.

OBJECTIVE: To describe challenges in diagnosis and management of patients with clinical syndromes of immune reconstitution inflammatory syndrome (IRIS) involving the CNS. METHODS: The authors describe three patients with clinically distinct neurologic manifestations of IRIS with HIV infection who presented as diagnostic and therapeutic challenges. RESULTS: One patient with cryptococcal meningitis developed acute cerebellitis with mass effect and brainstem compression. Corticosteroid therapy was associated with complete resolution of the cerebellar lesion but the patient developed VZV encephalitis. Another patient with progressive multifocal leukoencephalopathy developed subacute progression of focal neurologic deficits associated with contrast enhancing lesions on brain MRI. This patient had spontaneous resolution of the lesion but was left with residual deficits. One patient developed a progressive dementing syndrome and deterioration over several months resulting in coma during combination antiretroviral therapy. A brain biopsy in this latter patient showed massive infiltration of T lymphocytes predominantly of the CD8 subtype. This patient had a significant improvement with corticosteroids and change in antiretroviral regimen although she was left with residual cognitive impairment. CONCLUSIONS: Immune reconstitution inflammatory syndrome should be suspected in patients who show clinical or radiologic deterioration following initiation of antiretroviral therapy accompanied with improvement in CD4 cell count and viral load. Some patients may respond to a brief course of treatment with corticosteroids.

IgG isolated from LP-BM5 infected mouse brain activates ionotropic glutamate receptors.

Biochemical and immunological studies have shown that mice infected with LP-BM5 virus develop antibodies to ionotropic glutamate receptors. Here, IgG isolated from brain of infected mice has been tested electrophysiologically on cultured rat cortical and hippocampal neurons. The IgG elicited glycine-independent currents that reversed at approximately 0 mV. Equivalent concentrations of IgG from uninfected mice were inactive. The glycine-independent currents were less influenced by DNQX and GYKI-52466 than currents elicited by AMPA and KA. The IgG also elicited glycine-dependent currents that reversed at -10 mV and were blocked by dl-AP5, 5,7-DCKA, and polyamine amides. Glycine-dependent and -independent currents were unaffected by tetrodotoxin, strychnine, the transmembrane Cl- gradient or d-tubocurare. Although part of the glycine-independent current remains uncharacterized, these results confirm that a virus-induced immunopathology produces IgG clones that activate ionotropic glutamate receptors and that could, thereby, contribute to the excitotoxic neurological syndrome observed in LP-BM5-infected mice.

Virus-induced autoimmunity: epitope spreading to myelin autoepitopes in Theiler's virus infection of the central nervous system.

Epidemiological studies indicate that host immunogenetics and history of infection, particularly by viruses, may be a necessary cofactor for the induction of a variety of autoimmune diseases. To date, however, there is no clear-cut evidence, either in experimental animal models or in human autoimmune disease, that supports either molecular mimicry (Wucherpfennig and Strominger, 1995; Fujinami and Oldstone, 1985) or a role for superantigens (Scherer et al., 1993) in the initiation of T cell-mediated autoimmunity. In contrast, the current data provide compelling evidence in support of a major role for epitope spreading in the induction of myelin-specific autoimmunity in mice persistently infected with TMEV. It is significant that two picornaviruses closely related to TMEV, coxsackievirus (Rose and Hill, 1996) and encephalomyocarditis virus (EMCV) (Kyu et al., 1992), have been similarly shown to persist (either the viral RNA or the infectious virus) in their target organs and have been associated with the development of chronic autoimmune diseases, including myocarditis and diabetes. Thus, inflammatory responses induced by viruses that trigger proinflammatory Th1 responses, and have the ability to persist in genetically susceptible hosts, may lead to chronic organ-specific autoimmune disease via epitope spreading. Epitope spreading has important implications for the design of antigen-specific therapies for the potential treatment of MS and other autoimmune diseases. This process indicates that autoimmune diseases are evolving entities and that the specificity of the effector autoantigen-specific T cells varies during the chronic disease process. Our experiments employing tolerance in R-EAE clearly indicate that antigen-specific treatment of ongoing disease is possible for preventing disease relapses, provided the proper relapse-associated epitope is targeted (Vanderlugt et al., 1999). However, the ability to identify relapse-associated epitopes in humans will be a difficult task because immunodominance will vary in every individual. The use of costimulatory antagonists that can induce anergy without requiring prior knowledge of the exact epitopes (Miller et al., 1995b), or the use of therapies that induce bystander suppression (Nicholson et al., 1997; Brocke et al., 1996), may thus be more practical current alternative therapies for the treatment of human autoimmune disease.