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A single amino acid substitution in the cyclin D binding domain of the infected cell protein no. 0 abrogates the neuroinvasiveness of herpes simplex virus without affecting its ability to replicate

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 1999年第14期96卷 8184-8189页

作者： Van Sant, C Kawaguchi, Y Roizman, B Univ Chicago Marjorie B Kovler Viral Oncol Labs Chicago IL 60637 USA

The infected cell protein no, 0 (ICP0) of herpes simplex virus 1 is a promiscuous transactivator shown to enhance the expression of genes introduced into cells by infection or transfection. The protein interacts with several viral and cellular proteins. Earlier studies have shown that ICP0 binds and stabilizes cyclin D3 but does interfere with the phosphorylation of retinoblastoma protein, its major function. Cyclin D3 plays a key role in the transition from GI to S phase. To define the role of cyclin D3 in productive infection, the ICP0 binding site for cyclin D3 was mapped and mutagenized by substitution of aspartic acid codon 199 with the alanine codon. We report that the substitution precluded the interaction of this protein with cyclin D3 in the yeast two-hybrid system and the stabilization of cyclin D3 in infected cells, A recombinant virus carrying this mutation could not be differentiated from wild-type parent with respect to replication in dividing cells but yielded 10-fold less progeny from infected resting cells and serum-deprived or contact-inhibited human fibroblasts, In mice, the mutant was only slightly less pathogenic than the wild-type parent by intracerebral route but was significantly less neuroinvasive after peripheral inoculation. Replacement of the mutated amino acid with aspartic acid restored wild-type phenotype. Stabilization of cyclin D3 therefore is linked to higher:virus yields in nondividing cells and potentially higher virulence in experimental and natural hosts, One function of ICP0 is to scavenge the cell for proteins that could bolster viral replication.

关键词：氨基酸取代天冬氨酸结合部位细胞培养的中枢神经系统/病毒学黑长尾猴密码子接触抑制细胞周期蛋白D3 细胞周期蛋白类/代谢基因组病毒 HeLa细胞疱疹病毒1型人/遗传学疱疹病毒1型人/致病力疱疹病毒1型人/生理学即早蛋白质类/化学即早蛋白质类/代谢诱变定点磷酰化重组蛋白质类/化学重组蛋白质类/代谢重组遗传视网膜母细胞瘤蛋白质/代谢皮肤/病毒学肿瘤细胞培养的泛素蛋白连接酶类 Vero细胞毒力病毒复制动物人类小鼠兔

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The invasion routes of neurovirulent A Hong Kong 483/97 (H5N1) influenza virus into the central nervous system after respiratory infection in mice

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ARCHIVES OF VIROLOGY 2002年第7期147卷 1425-1436页

作者： Park, CH Ishinaka, M Takada, A Kida, H Kimura, T Ochiai, K Umemura, T Hokkaido Univ Lab Comparat Pathol Sapporo Hokkaido Japan Hokkaido Univ Grad Sch Vet Med Microbiol Lab Sapporo Hokkaido Japan Univ Tokyo Inst Med Sci Div Virol Tokyo Japan

A/Hong Kong/483/97 (H5N1) influenza virus (HK483) isolated from the third patient during the outbreak of chicken and human influenza in Hong Kong in 1997 was shown to be neurovirulent in mice. HK483 was inoculated intranasally to mice, and the invasion routes of the virus in the central nervous system (CNS) were investigated by immunohistochemical and in situ hybridization. The pathological changes consisted of bronchopneumonia, ganglionitis, and nonpurulent encephalomyelitis of the brain stem and the anterior part of the thoracic cord. Viral antigens and viral nucleic acids (RNA and mRNA) were demonstrated in the pterygopalatine, trigeminal and superior ganglions prior to or simultaneously with their detection in the CNS. The antigens and nucleic acids were also observed in the olfactory bulb from an early stage of the infection. In the spinal cord, virus-infected cells were first demonstrated in the grey matter of the thoracic cord. The virus, which primarily replicated in the lungs, was considered to invade the thoracic cord via cardiopulmonary splanchnic nerves and sympathetic nerves. These findings indicate that the virus reached the CNS through afferent fibers of the olfactory, vagal, trigeminal, and sympathetic nerves following replication in the respiratory mucosa.

关键词：抗原病毒/分析脑干/病毒学支气管肺炎/病理学支气管肺炎/病毒学中枢神经系统/病理学中枢神经系统/病毒学疾病模型动物脑脊髓炎/病理学脑脊髓炎/病毒学神经节交感/病毒学免疫组织化学原位杂交肺/病理学肺/病毒学小鼠近交BALBC 嗅球/病毒学正黏病毒科/遗传学正黏病毒科/免疫学正黏病毒科/分离和提纯正黏病毒科感染/病理学正黏病毒科感染/病毒学 RNA 信使/分析 RNA 病毒/分析脊髓/病毒学时间因素动物人类男(雄)性小鼠

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A comparative study of pseudorabies virus (PRV) strains with defects in thymidine kinase and glycoprotein genes

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JOURNAL OF COMPARATIVE PATHOLOGY 2000年第2-3期123卷 152-163页

作者： Ferrari, M Mettenleiter, TC Romanelli, MG Cabassi, E Corradi, A Dal Mas, N Silini, R Ist Zooprofilatt Sperimentale Lombardia & Emilia I-25125 Brescia Italy Friedrich Loeffler Inst Fed Res Ctr Virus Dis Anim Insel Riems Germany Univ Verona Fac Med & Chirurg Ist Biol & Genet I-37100 Verona Italy Univ Parma Fac Med Vet Ist Anat Patol I-43100 Parma Italy Azienda Sanit Locale Brescia Italy

In the course of two experiments, an examination was made of the virulence and neuroinvasiveness for pigs of two pseudorabies virus mutants (strain 6C2TK(-), with a defect in thymidine kinase (TK) function;and strain 6C2TK(-), gI(-)/gE(-), with defects in TK and glycoproteins I and E) and of the wild-type parent strain (86/27V). At various times after intranasal inoculation, pigs were killed and samples of tonsil, lung and different levels of the trigeminal and olfactory nervous pathways were examined by methods that included viral isolation, polymerase chain reaction assay and immunohistochemistry. Both mutant viruses were of reduced virulence, as indicated by no more than moderate clinical signs and lesions, and only sporadic isolation of virus;moreover, unlike the wild-type parent strain, the mutant viruses were not reactivated from the latent state by corticosteroid treatment. In addition, migration of the mutant strains to the central nervous system (olfactory and trigeminal nervous pathways) was reduced as compared with that of the wild-type strain. Thus, mutations in the genes encoding the TK enzyme and the gI/gE complex were associated with reduced virulence, reduced replication in peripheral target tissues, and reduced migration to the olfactory and trigeminal pathways. (C) 2000 Harcourt Publishers Ltd.

关键词：抗体病毒/血液抗体病毒/药物作用抗原病毒/分析细胞系中枢神经系统/病理学中枢神经系统/病毒学 DNA 病毒/遗传学地塞米松/治疗应用疱疹病毒1型猪/遗传学疱疹病毒1型猪/免疫学疱疹病毒1型猪/致病力免疫组织化学突变嗅球/病理学嗅球/病毒学聚合酶链反应假性狂犬病/病理学假性狂犬病/预防和控制假性狂犬病/病毒学猪胸苷激酶/遗传学时间因素三叉神经节/病理学三叉神经节/病毒学病毒包膜蛋白质类/遗传学毒力/遗传学病毒激活/遗传学病毒潜伏期/遗传学动物

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Recombinant adeno-associated virus type 2, 4, and 5 vectors: Transduction of variant cell types and regions in the mammalian central nervous system

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2000年第7期97卷 3428-3432页

作者： Davidson, BL Stein, CS Heth, JA Martins, I Kotin, RM Derksen, TA Zabner, J Ghodsi, A Chiorini, JA Univ Iowa Coll Med Dept Internal Med Program Gene Therapy Iowa City IA 52242 USA Univ Iowa Coll Med Dept Neurol Iowa City IA 52242 USA Univ Iowa Coll Med Dept Neurosurg Iowa City IA 52242 USA NHLBI Mol Hematol Branch NIH Bethesda MD 20892 USA Natl Inst Dent & Craniofacial Res Gene Therapy & Therapeut Branch NIH Bethesda MD 20892 USA

Recombinant adeno-associated virus vectors based on serotype 2 (rAAV2) can direct transgene expression in the central nervous system (CNS), but it is not known how other rAAV serotypes perform as CNS gene transfer vectors. Serotypes 4 and 5 are distinct from rAAV2 and from each other in their capsid regions, suggesting that they may direct binding and entry into different cell types. In this study, we examined the tropisms and transduction efficiencies of P-galactosidase-encoding vectors made from rAAV4 and rAAV5 compared with similarly designed rAAV2-based vectors. Injection of rAAV5 beta-galactosidase (beta gal) or rAAV4 beta gal into the lateral ventricle resulted in stable transduction of ependymal cells, with approximately 10-fold more positive cells than in mice injected with rAAV2 beta gal. Major differences between the three vectors were revealed upon striatal injections. Intrastriatal injection of rAAV4 beta gal resulted again in striking ependyma-specific expression of transgene, with a notable absence of transduced cells in the parenchyma. rAAV2 beta gal and rAAV5 beta gal intrastriatal injections led to beta-gal-positive parenchymal cells, but unlike rAAV2 beta gal, rAAV5 beta gal transduced both neurons and astrocytes. The number of transgene-positive cells in rAAV5 beta gal-injected brains was 130 and 5,000 times higher than in rAAV2 beta gal-injected brains at 3 and 15 wk, respectively. Moreover, transgene-positive cells were widely dispersed throughout the injected hemisphere in rAAV5 beta gal-transduced animals. Together, our data provide in vivo support for earlier in vitro work, suggesting that rAAV4 and rAAV5 gain cell entry by means of receptors distinct from rAAV2. These differences could be exploited to improve gene therapy for CNS disorders.

关键词：中枢神经系统/细胞学中枢神经系统/病毒学依赖病毒/遗传学遗传载体免疫组织化学小鼠近交C57BL 重组遗传转导遗传 β半乳糖苷酶类/遗传学动物男(雄)性小鼠

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Nipah virus infection - Pathology and pathogenesis of an emerging paramyxoviral zoonosis

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AMERICAN JOURNAL OF PATHOLOGY 2002年第6期161卷 2153-2167页

作者： Wong, KT Shieh, WJ Kumar, S Norain, K Abdullah, W Guarner, J Goldsmith, CS Chua, KB Lam, SK Tan, CT Goh, KJ Chong, HT Jusoh, R Rollin, PE Ksiazek, TG Zaki, SR Ctr Dis Control & Prevent Infect Dis Pathol Act Natl Ctr Infect Dis Atlanta GA 30333 USA Minist Hlth Kuala Lumpur Malaysia Univ Malaya Kuala Lumpur Malaysia

In 1998, an outbreak of acute encephalitis with high mortality rates among pig handlers in Malaysia led to the discovery of a novel paramyxovirus named Nipah virus. A multidisciplinary investigation that included epidemiology, microbiology, molecular biology, and pathology was pivotal in the discovery of this new human infection. Clinical and autopsy findings were derived from a series of 32 fatal human cases of Nipah virus infection. Diagnosis was established in all cases by a combination of immunohistochemistry (IHC) and serology. Routine histological stains, IHC, and electron microscopy were used to examine autopsy tissues. The main histopathological. findings included a systemic vasculitis with extensive thrombosis and parenchymal necrosis, particularly in the central nervous system. Endothelial cell damage, necrosis, and syncytial giant cell formation were seen in affected vessels. Characteristic viral inclusions were seen by light and electron microscopy. IHC analysis showed widespread presence of Nipah virus antigens in endothelial and smooth muscle cells of blood vessels. Abundant viral antigens were also seen in various parenchymal cells, particularly in neurons. Infection of endothelial cells and neurons as well as vasculitis and thrombosis seem to be critical to the pathogenesis of this new human disease.

关键词：亚洲东南部/流行病学血管/病理学血管/病毒学中枢神经系统/病理学中枢神经系统/病毒学中枢神经系统病毒感染/诊断中枢神经系统病毒感染/流行病学中枢神经系统病毒感染/病理学中枢神经系统病毒感染/病毒学传染病新出现/诊断传染病新出现/流行病学传染病新出现/病理学传染病新出现/病毒学疾病暴发流行神经元/病毒学副黏病毒科感染/诊断副黏病毒科感染/流行病学副黏病毒科感染/病理学副黏病毒科感染/病毒学副黏病毒亚科/生理学猪动物传染病青少年成年人老年人动物女(雌)性人类男(雄)性中年人

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The two faces of HIV infection of cerebrospinal fluid

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TRENDS IN MICROBIOLOGY 2000年第9期8卷 387-390页

作者： Price, RW Univ Calif San Francisco Dept Neurol San Francisco CA 94110 USA San Francisco Gen Hosp Neurol Serv San Francisco CA 94110 USA

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Acute hemiplegia associated with herpes zoster infection in children: Report of one case

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PEDIATRIC NEUROLOGY 2000年第4期23卷 345-348页

作者： Hung, PY Lee, WT Shen, YZ Natl Taiwan Univ Dept Pediat Taipei 10764 Taiwan

Herpes tester infection has been rarely reported to cause angiitis of the central nervous system in children, We describe a 4-year, 8-month-old female with acute hemiplegia and central facial palsy 6 weeks after she had had tester ophthalmicus. The findings of magnetic resonance angiography, the clinical picture, and a preceding history of herpes tester ophthalmicus suggested tester vasculitis. Herpes tester vasculitis is thus another consideration when examining a child with acute hemiplegia and a recent herpes tester infection. (C) 2000 by Elsevier Science Inc. All rights reserved.

关键词：面神经麻痹/病毒学偏瘫/病因学偏瘫/病毒学疱疹带状眼部/并发症疱疹病毒3型人磁共振血管造影术磁共振成像血管炎中枢神经系统/并发症血管炎中枢神经系统/诊断血管炎中枢神经系统/病毒学儿童学龄前女(雌)性人类

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