病毒与肥胖

近年研究表明 ,病毒与肥胖有密切关系。迄今为止 ,经动物实验发现 6种病毒与肥胖有关 ,即犬瘟热病毒、Rous相关病毒 7、博纳病病毒和羊痢疾病毒 ,另外 ,SMAM 1禽类腺病毒和人类 36型腺病毒可导致人类肥胖。大多数病毒诱导肥胖可能是通过神经内分泌网络和 (或 )调节瘦素的表达实现的     

寨卡病毒动物感染模型研究进展

寨卡病毒是一种经由蚊媒传播的重要的黄病毒属病毒,已导致全球数百万人感染,引发严峻的公共卫生危机。2015年以来,尤其是中南美洲地区暴发的寨卡疫情出现了新生儿小头畸形、大脑发育异常与格林巴列综合征等不同以往的严重症状,引发高度关注。合适的动物感染模型对于研究寨卡病毒的传播方式、致病机理及研发防控寨卡病毒感染的新药、疫苗及诊断试剂等都有十分重要的意义。本文就近年来建立的寨卡病毒动物感染模型进展进行综述。     

病毒与肥胖

近年研究表明，病毒与肥胖有密切关系。迄今为止，经动物实验发现6种病毒与肥胖有关，即犬瘟热病毒、Rous相关病毒－7、博纳病病毒和羊痢疾病毒，另外，SMAM－1禽类腺病毒和人类36型腺病毒可导致人类肥胖。大多数病毒诱导肥胖可能是通过神经内分泌网络和（或）调节瘦素的表达实现的。     

麻疹病毒感染与免疫

麻疹病毒是一种15k bp,被膜的负链RNA病毒,副粘病毒科,麻疹病毒属.麻疹病毒只感染人等灵长目动物,它是一种稳定的单型病毒,难以彻底清除.     

狂犬病病毒和犬瘟热病毒疫苗株混合感染Vero细胞的实验研究

目的研究狂犬病病毒(RV)及犬瘟热病毒(CDV)共同感染Vero细胞及混合感染对产毒量的影响,比较病毒检测方法的敏感性。方法将单独培养的RV、CDV及RV-CDV混合培养物进行连续10倍稀释后同步接种Vero细胞,37℃5%CO2培养5d,分别以直接免疫荧光(DFA)、RT-PCR及荧光定量RT-PCR方法检测病毒的半数细胞感染量,并对各病毒检测方法进行比较。结果RV和CDV可同时感染Vero细胞,并在其中增殖。CDV单独感染Vero细胞的TCID50为10-5.8/0.05ml,RV和CDV混合感染Vero细胞的TCID50为10-5.5/0.05ml。DFA、RT-PCR和荧光定量RT-PCR阳性的RV-CDV感染最大稀释度分别为10-6、10-5和10-6。结论混合培养对RV和CDV的感染滴度及产毒量影响很小。免疫荧光灶检测与RT-PCR及荧光定量RT-PCR方法检测的敏感性相当。犬瘟热-狂犬病毒联合疫苗的病毒滴度检测可不经中和其中的一个病毒直接将联合疫苗接种Vero细胞,然后分别进行免疫荧光检测。     

麻疹病毒属病毒检测基因芯片的建立

目的建立主要麻疹病毒属病毒(麻疹病毒、犬瘟热病毒、小反刍兽疫病毒、牛瘟病毒、海豹瘟热病毒、海豚瘟热病毒等)种特异性检测基因芯片。方法应用生物信息学方法从GenBank获得麻疹病毒属病毒的全部基因组序列,以Primer Premier5.0软件设计针对上述病毒的寡核苷酸探针并制备基因芯片,以上述6种病毒及犬副流感病毒、VERO细胞及健康犬组织等验证寡核苷酸芯片的特异性,以细胞毒和临床病料检测基因芯片的灵敏度、特异性和重复性,芯片制备后低温放置3、6、12个月后检验其检测稳定性。结果基因芯片检测到麻疹病毒属病毒种特异性信号,无杂信号及交叉信号,芯片方法的灵敏度为10-2TCID50,是PCR的100倍,病料检测与PCR相符率为100%。结论初步建立了麻疹病毒属病毒种特异性基因芯片,该方法灵敏度高,特异性强,适用于麻疹病毒属的流行病学调查和种特异性鉴定。     

《2016年欧洲儿童胃肠、肝病和营养学会委员会意见书:儿童戊型肝炎》推荐意见

戊型肝炎病毒(HEV)是一种单链、无包膜的RNA病毒,属于肝炎病毒属戊型肝炎病毒科.目前已知的可感染人类的HEV有4种不同的基因型(1～4型),详见表1.HEV基因1型主要在亚洲、非洲流行,而基因2型主要在非洲、中美洲流行.最近有报道显示猪可作为基因1型的动物宿主,目前尚不知基因2型的动物宿主.基因3型主要流行于欧洲和北美,它能感染多种动物,被认为是一种人畜共患感染的病毒.基因4型已在东南亚与欧洲的马蝇中被发现.     

巨细胞病毒在动脉粥样硬化中的作用

巨细胞病毒 (CMV)对人和动物的感染相当普遍。自从 1 985年 Fabricant报道用禽类疱疹病毒诱发火鸡冠状动脉粥样硬化 (AS)以来 ,CMV与 AS的关系得到了广泛的研究。1　 CMV的分子生物学特点CMV属疱疹病毒科 ,是巨细胞包涵体病病原体 ,对人和多种动物具有种特异性 ,感染人类的为人巨细胞病毒 (HCMV)。 CMV复制相当缓慢 ,感染后绝大多数情况下为隐性感染状态。CMV核酸为线状双链脱氧核糖核酸 (DNA) ,含 2 4 0 kb,由一个长独特序列 (Ul)和一个短独特序列 (Us)构成 ,Ul与 Us可以倒向连接使病毒出现 4种结构类型的基因组。CMV基因组…     

汉坦病毒依赖RNA的RNA聚合酶研究进展

汉坦病毒（Hantavirus，HV）属于布尼亚病毒科（Bunyaviridae）汉坦病毒属，是单链、分节段的负链RNA病毒，其基因组由大（Large，L）、中（Medium，M）、小（Small，S）3个片段组成。分别编码病毒依赖RNA的RNA聚合酶（L蛋白）、G1和G2糖蛋白、核衣壳蛋白（NP）。汉坦病毒由啮齿类动物携带，在宿主动物中产生非致病性持续性感染，可以经过啮齿类动物排放的病毒污染的气溶胶等多种途径感染人类。     

猪细小病毒的致病机制与防控策略

猪细小病毒(porcine parvovirus,PPV)是细小病毒科细小病毒属的成员,引起初孕母猪的繁殖障碍、仔猪的皮肤炎症和肠炎性腹泻.这些疾病在临床表现和病理特点上各不相同.近年来,PPV与其他病毒混合感染发生较多,是导致很多疾病综合征的病原之一.本文主要针对猪细小病毒的病原、致病机制和防控策略做一综述,以期对动物细小病毒病的防治提供的借鉴.     

A canine distemper model of virus-induced anergy.

For development of an animal model of virus-induced anergy, the effect of canine distemper virus (CDV) upon cell-mediated immunity in dogs was investigated. First, canine cutaneous reactions and in vitro lymphocyte responses to soluble protein antigens were characterized. Dogs immunized with picryl guinea pig albumin and with keyhole limpet hemocyanin (both in complete Freund's adjuvant) responded reproducibly to intracutaneous challenge with these antigens. Reactivity peaked in 20-40 days (maximal induration, 6-50 mm). Lymphocytes from these animals responded in vitro to stimulation with keyhole limpet hemocyanin or purified protein derivative. This stimulation was antigen-specific and was maximal on day 6 of culture. Infection with CDV depressed cutaneous reactivity and lymphocyte response in vitro to antigens and mitogens. This effect was transient in animals previously vaccinated with attenuated CDV; however, gnotobiotic puppies (susceptible to CDV) had prolonged depression of cell-mediated immunity and lymphopenia. Some of these animals developed neurologic symptoms and died. The findings indicate that CDV infection is a potentially useful model for study of virus-induced depression of T (thymus)-cell responses and support the hypothesis that there is more than one mechanism responsible for this phenomenon.     

Development of CMX001 for the Treatment of Poxvirus Infections

CMX001 (phosphonic acid, [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl)ethoxy]methyl]mono[3-(hexadecyloxy)propyl] ester) is a lipid conjugate of the acyclic nucleotide phosphonate, cidofovir (CDV). CMX001 is currently in Phase II clinical trials for the prophylaxis of human cytomegalovirus infection and under development using the Animal Rule for smallpox infection. It has proven effective in reduction of morbidity and mortality in animal models of human smallpox, even after the onset of lesions and other clinical signs of disease. CMX001 and CDV are active against all five families of double-stranded DNA (dsDNA) viruses that cause human morbidity and mortality, including orthopoxviruses such as variola virus, the cause of human smallpox. However, the clinical utility of CDV is limited by the requirement for intravenous dosing and a high incidence of acute kidney toxicity. The risk of nephrotoxicity necessitates pre-hydration and probenecid administration in a health care facility, further complicating high volume CDV use in an emergency situation. Compared with CDV, CMX001 has a number of advantages for treatment of smallpox in an emergency including greater potency in vitro against all dsDNA viruses that cause human disease, a high genetic barrier to resistance, convenient oral administration as a tablet or liquid, and no evidence to date of nephrotoxicity in either animals or humans. The apparent lack of nephrotoxicity observed with CMX001 in vivo is because it is not a substrate for the human organic anion transporters that actively secrete CDV into kidney cells. The ability to test the safety and efficacy of CMX001 in patients with life-threatening dsDNA virus infections which share many basic traits with variola is a major advantage in the development of this antiviral for a smallpox indication.     

Comparable Infection Level and Tropism of Measles Virus and Canine Distemper Virus in Organotypic Brain Slice Cultures Obtained from Natural Host Species

Measles virus (MV) and canine distemper virus (CDV) are closely related members of the family Paramyxoviridae, genus Morbillivirus. MV infection of humans and non-human primates (NHPs) results in a self-limiting disease, which rarely involves central nervous system (CNS) complications. In contrast, infection of carnivores with CDV usually results in severe disease, in which CNS complications are common and the case-fatality rate is high. To compare the neurovirulence and neurotropism of MV and CDV, we established a short-term organotypic brain slice culture system of the olfactory bulb, hippocampus, or cortex obtained from NHPs, dogs, and ferrets. Slices were inoculated ex vivo with wild-type-based recombinant CDV or MV expressing a fluorescent reporter protein. The infection level of both morbilliviruses was determined at different times post-infection. We observed equivalent infection levels and identified microglia as main target cells in CDV-inoculated carnivore and MV-inoculated NHP brain tissue slices. Neurons were also susceptible to MV infection in NHP brain slice cultures. Our findings suggest that MV and CDV have comparable neurotropism and intrinsic capacity to infect CNS-resident cells of their natural host species.     

Cidofovir as primary pre-emptive therapy for post-transplant cytomegalovirus infections.

Pre-emptive antiviral therapy for CMV infection following allogeneic stem cell transplantation is an effective strategy for preventing CMV disease. This entails the logistic difficulty of daily intravenous therapy with ganciclovir or foscarnet to clinically asymptomatic patients. Cidofovir (CDV) is effective against CMV in vitro and has the practical advantage of weekly administration. However, there are limited data on the pre-emptive use of CDV in CMV infections. We carried out a pilot study exploring the efficacy and toxicity of CDV as primary pre-emptive therapy for CMV infections monitored by PCR-based assays. CDV was used at 5 mg/kg with probenecid and hydration, weekly for a maximum of 4 weeks, followed by fortnightly maintenance treatment. Four patients were treated with CDV and two of them responded. Both the non-responders developed CMV disease. There was no renal toxicity noted in any of the patients, but three patients had severe vomiting and one developed uveitis, which precluded maintenance treatment in the two responders. Following failure of CDV, foscarnet was effective in controlling the CMV infection in both patients, although the infection recurred in both. Thus, larger randomised studies are required before CDV can be recommended as a primary pre-emptive therapy for post-transplant CMV infections.     

Cidofovir for treating adenoviral hemorrhagic cystitis in hematopoietic stem cell transplant recipients

Adenovirus (AdV) infection is an important cause of morbidity and mortality in hematopoietic stem cell transplant (HSCT) recipients. We treated 16 patients with AdV hemorrhagic cystitis (HC) following HSCT with cidofovir (CDV; 1 mg/kg/day, three times weekly for 3 weeks). Patients included 10 males and six females with a median age of 50 years (range 10-62). Two of the 16 patients were unevaluable because of early death from nonadenoviral causes. CDV therapy cleared AdV from urine in 12 of 14 patients (86%). Of 14 patients, 10 (71%) showed clinical improvements in HC. Among 14 patients, seven (50%) had avoided renal damage, the most important CDV toxicity. One patient previously treated with foscarnet for cytomegalovirus (CMV) required hemodialysis, and CDV treatment was discontinued. In another patient, CDV treatment was discontinued because of grade 2 nephrotoxicity. Four patients became positive for CMV antigenemia while being treated with CDV, and two developed herpes simplex virus (HSV) stomatitis while being treated with CDV. CDV proved effective in treating AdV HC in transplant patients. However, CDV at 1 mg/kg/day given three times weekly failed to prevent breakthrough infection with CMV and HSV in some patients.     

A Canine Distemper Virus Retrospective Study Conducted from 2011 to 2019 in Central Italy (Latium and Tuscany Regions)

Canine distemper virus (CDV) is a highly lethal contagious viral pathogen mainly found in domestic and wild canids and mustelids. Although, in Italy, circulating strains of Europe 1, Europe wildlife and Arctic type are reported, data relating to Latium and Tuscany regions are limited. In view of this, through passive surveillance, we investigated the presence of CDV and which strains were circulating in these Regions. From March 2017 to October 2019, a group of 122 subjects were tested for CDV using a PCR protocol described in the literature, with 12 detected positive; analyses were carried out on a set of target samples (brain and lung, conjunctival, nasal and rectal swabs, urine or swab from bladder and intracardiac clot) that was defined for the detection of CDV in both live and dead animals. The rectal swab, easily collected also from live animals, represented the most suitable sample for CDV diagnosis, with 9 positive of the 11 (81.82%) tested. In addition, brain and lung of 15 subjects out of 181 susceptible animals collected between 2011 and 2018, during post mortem investigations in routine diagnostic activity, were CDV positive. Molecular analyses of all positive samples, using a 287 bp fragment located within the conserved N terminus of the morbillivirus nucleoprotein gene, detected the circulation of strain CDV599/2016 ({"type":"entrez-nucleotide","attrs":{"text":"KX545421.1","term_id":"1104313078"}}KX545421.1) belonging to the “Europe wildlife” lineage, and of strain {"type":"entrez-protein","attrs":{"text":"CDV12254","term_id":"815621404"}}CDV12254/2015 ({"type":"entrez-nucleotide","attrs":{"text":"KX024709.1","term_id":"1031961714"}}KX024709.1), belonging to the Arctic-lineage, thus confirming the co-circulation of the two lineages, as already noted in previous studies.     

Synthesis and early development of hexadecyloxypropylcidofovir: an oral antipoxvirus nucleoside phosphonate

Hexadecyloxypropyl-cidofovir (HDP-CDV) is a novel ether lipid conjugate of (S)-1-(3-hydroxy-2-phosphonoylmethoxypropyl)-cytosine (CDV) which exhibits a remarkable increase in antiviral activity against orthopoxviruses compared with CDV. In contrast to CDV, HDP-CDV is orally active and lacks the nephrotoxicity of CDV itself. Increased oral bioavailability and increased cellular uptake is facilitated by the lipid portion of the molecule which is responsible for the improved activity profile. The lipid portion of HDP-CDV is cleaved in the cell, releasing CDV which is converted to CDV diphosphate, the active metabolite. HDP-CDV is a highly effective agent against a variety of orthopoxvirus infections in animal models of disease including vaccinia, cowpox, rabbitpox and ectromelia. Its activity was recently demonstrated in a case of human disseminated vaccinia infection after it was added to a multiple drug regimen. In addition to the activity against orthopoxviruses, HDP-CDV (CMX001) is active against all double stranded DNA viruses including CMV, HSV-1, HSV-2, EBV, adenovirus, BK virus, orf, JC, and papilloma viruses, and is under clinical evaluation as a treatment for human infections with these agents.     

Tropism illuminated: lymphocyte-based pathways blazed by lethal morbillivirus through the host immune system

The immunosuppressive properties of morbilliviruses including measles and canine distemper virus (CDV) are well known, but the host cells supporting infection are poorly characterized. To identify these cells, a recombinant CDV expressing green fluorescent protein was produced by reverse genetics based on a wild-type strain lethal for ferrets. This recombinant virus fully retained virulence and blazed three lymphocyte-based pathways through the immune system of its host: first, it infected rapidly and massively circulating B and T cells; second, it took over and damaged secondary lymphatic organs including spleen, lymph nodes, and gut-associated and mucosal lymphoid tissues; third, it infected most thymocytes. In contrast, replication in epithelial cells was initially not detectable, but substantial before host death. Thus, CDV initially infects lymphocytes and massively replicates therein, thereby causing immunosuppression and preparing systemic invasion and host escape.     

Dual infection with polyomavirus BK and acyclovir-resistant herpes simplex virus successfully treated with cidofovir in a bone marrow transplant recipient

A hematopoietic stem cell transplant recipient developed a mucosal herpes simplex virus-1 (HSV-1) infection while under acyclovir (ACV) treatment (HSV was later shown to be resistant to ACV). Concomitantly, the patient presented a hemorrhagic cystitis (HC) due to polyomavirus BK, for which intravenous cidofovir (CDV) was prescribed. The patient benefited from the broad-spectrum anti-DNA virus activity of CDV, and not only the HC resolved without signs of nephrotoxicity but also the HSV-1 lesions disappeared. This is the first report describing the effect of CDV on 2 simultaneous and unrelated DNA viral infections in an immunosuppressed transplant recipient. In addition, we describe here that this HSV-1 isolate possesses a unique phenotype and genotype.     

Efficacy of CMX001 as a prophylactic and presymptomatic antiviral agent in New Zealand white rabbits infected with rabbitpox virus, a model for orthopoxvirus infections of humans

CMX001, a lipophilic nucleotide analog formed by covalently linking 3-(hexdecyloxy)propan-1-ol to cidofovir (CDV), is being developed as a treatment for smallpox. CMX001 has dramatically increased potency versus CDV against all dsDNA viruses and, in contrast to CDV, is orally available and has shown no evidence of nephrotoxicity in healthy volunteers or severely ill transplant patients to date. Although smallpox has been eliminated from the environment, treatments are urgently being sought due to the risk of smallpox being used as a bioterrorism agent and for monkeypox virus, a zoonotic disease of Africa, and adverse reactions to smallpox virus vaccinations. In the absence of human cases of smallpox, new treatments must be tested for efficacy in animal models. Here we first review and discuss the rabbitpox virus (RPV) infection of New Zealand White rabbits as a model for smallpox to test the efficacy of CMX001 as a prophylactic and early disease antiviral. Our results should also be applicable to monkeypox virus infections and for treatment of adverse reactions to smallpox vaccination.