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1.
Arch Virol ; 160(5): 1153-61, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25701211

RESUMO

In this study we describe that six rat models (SD, WIST, LEW, BN, F344 and DA) are susceptible to intravaginal herpes simplex virus-2 (HSV-2) infection after pre-treatment with progesterone. At a virus dose of 5 × 10(6) PFU of HSV-2, all rat models were infected presenting anti-HSV-2 antibodies, infectious virus in vaginal washes, and HSV-2 DNA genome copies in lumbosacral dorsal root ganglia and the spinal cord. Most of the LEW, BN, F344, and DA rats succumbed in systemic progressive symptoms at day 8-14 post infection, but presented no or mild genital inflammation while SD and WIST rats were mostly infected asymptomatically. Infected SD rats did not reactivate HSV-2 spontaneously or after cortisone treatment. In an HSV-2 virus dose reduction study, F344 rats were shown to be most susceptible. We also investigated whether an attenuated HSV-1 strain (KOS321) given intravaginally, could protect from a subsequent HSV-2 infection. All LEW, BN, and F344 rats survived a primary HSV-1 infection and no neuronal infection was established. In BN and F344 rats, anti-HSV-1 antibodies were readily detected while LEW rats were seronegative. In contrast to naïve LEW, BN, and F344 rats where only 3 of 18 animals survived 5 × 10(6) PFU of HSV-2, 23 of 25 previously HSV-1 infected rats survived a challenge with HSV-2. The described models provide a new approach to investigate protective effects of anti-viral microbicides and vaccine candidates, as well as to study asymptomatic primary genital HSV-2 infection.


Assuntos
Modelos Animais de Doenças , Herpes Genital/patologia , Herpes Genital/virologia , Herpesvirus Humano 1/crescimento & desenvolvimento , Herpesvirus Humano 2/crescimento & desenvolvimento , Animais , Anticorpos Antivirais/sangue , Feminino , Ratos , Análise de Sobrevida , Vagina/virologia
2.
J Virol ; 87(21): 11525-37, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23966380

RESUMO

We previously identified two novel endogenous murine leukemia virus proviruses, PreXMRV-1 and PreXMRV-2, and showed that they most likely recombined during xenograft passaging of a human prostate tumor in mice to generate xenotropic murine leukemia virus-related virus (XMRV). To determine the recombination potential of PreXMRV-1 and PreXMRV-2, we examined the generation of replication-competent retroviruses (RCRs) over time in a cell culture system. We observed that either virus alone was noninfectious and the RNA transcripts of the viruses were undetectable in the blood and spleen of nude mice that carry them. To determine their potential to generate RCRs through recombination, we transfected PreXMRV-1 and PreXMRV-2 into 293T cells and used the virus produced to infect fresh cells; the presence of reverse transcriptase activity at 10 days postinfection indicated the presence of RCRs. Population sequencing of proviral DNA indicated that all RCRs contained the gag and 5' half of pol from PreXMRV-2 and the long terminal repeat, 3' half of pol (including integrase), and env from PreXMRV-1. All crossovers were within sequences of at least 9 identical nucleotides, and crossovers within each of two selected recombination zones of 415 nucleotides (nt) in the 5' untranslated region and 982 nt in pol were required to generate RCRs. A recombinant with the same genotype as XMRV was not detected, and our analysis indicates that the probability of generating an identical RCR is vanishingly small. In addition, the studies indicate that the process of RCR formation is primarily driven by selection for viable cis and trans elements from the parental proviruses.


Assuntos
Recombinação Genética , Replicação Viral , Vírus Relacionado ao Vírus Xenotrópico da Leucemia Murina/fisiologia , Estruturas Animais/virologia , Animais , Linhagem Celular , Cruzamentos Genéticos , DNA Viral/química , DNA Viral/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Dados de Sequência Molecular , Análise de Sequência de DNA , Proteínas Virais/genética , Vírus Relacionado ao Vírus Xenotrópico da Leucemia Murina/genética
3.
J Virol ; 86(1): 328-38, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22031947

RESUMO

Xenotropic murine leukemia virus-related virus (XMRV) was previously reported to be associated with human prostate cancer and chronic fatigue syndrome. Our groups recently showed that XMRV was created through recombination between two endogenous murine retroviruses, PreXMRV-1 and PreXMRV-2, during the passaging of a prostate tumor xenograft in nude mice. Here, multiple approaches that led to the identification of PreXMRV-2, as well as the distribution of both parental proviruses among different mouse species, are described. The chromosomal loci of both proviruses were determined in the mouse genome, and integration site information was used to analyze the distribution of both proviruses in 48 laboratory mouse strains and 46 wild-derived strains. The strain distributions of PreXMRV-1 and PreXMRV-2 are quite different, the former being found predominantly in Asian mice and the latter in European mice, making it unlikely that the two XMRV ancestors could have recombined independently in the wild to generate an infectious virus. XMRV was not present in any of the mouse strains tested, and among the wild-derived mouse strains analyzed, not a single mouse carried both parental proviruses. Interestingly, PreXMRV-1 and PreXMRV-2 were found together in three laboratory strains, Hsd nude, NU/NU, and C57BR/cd, consistent with previous data that the recombination event that led to the generation of XMRV could have occurred only in the laboratory. The three laboratory strains carried the Xpr1(n) receptor variant nonpermissive to XMRV and xenotropic murine leukemia virus (X-MLV) infection, suggesting that the xenografted human tumor cells were required for the resulting XMRV recombinant to infect and propagate.


Assuntos
Camundongos/virologia , Provírus/genética , Infecções por Retroviridae/veterinária , Vírus Relacionado ao Vírus Xenotrópico da Leucemia Murina/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Mapeamento Cromossômico , Feminino , Humanos , Masculino , Camundongos/genética , Camundongos Endogâmicos , Dados de Sequência Molecular , Provírus/isolamento & purificação , Provírus/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores Virais/química , Receptores Virais/genética , Recombinação Genética , Infecções por Retroviridae/virologia , Alinhamento de Sequência , Integração Viral , Receptor do Retrovírus Politrópico e Xenotrópico , Vírus Relacionado ao Vírus Xenotrópico da Leucemia Murina/isolamento & purificação , Vírus Relacionado ao Vírus Xenotrópico da Leucemia Murina/fisiologia
4.
Neuropharmacology ; 115: 128-138, 2017 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-26987983

RESUMO

Modulation of metabotropic glutamate 2 (mGlu2) receptor function has huge potential for treating psychiatric and neurological diseases. Development of drugs acting on mGlu2 receptors depends on the development and use of translatable animal models of disease. We report here a stop codon mutation at cysteine 407 in Grm2 (cys407*) that is common in some Wistar rats. Therefore, researchers in this field need to be aware of strains with this mutation. Our genotypic survey found widespread prevalence of the mutation in commercial Wistar strains, particularly those known as Han Wistar. Such Han Wistar rats are ideal for research into the separate roles of mGlu2 and mGlu3 receptors in CNS function. Previous investigations, unknowingly using such mGlu2 receptor-lacking rats, provide insights into the role of mGlu2 receptors in behaviour. The Grm2 mutant rats, which dominate some selectively bred lines, display characteristics of altered emotionality, impulsivity and risk-related behaviours and increased voluntary alcohol intake compared with their mGlu2 receptor-competent counterparts. In addition, the data further emphasize the potential therapeutic role of mGlu2 receptors in psychiatric and neurological disease, and indicate novel methods of studying the role of mGlu2 and mGlu3 receptors. This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Cistina/genética , Emoções/fisiologia , Mutação/genética , Receptores de Glutamato Metabotrópico/genética , Assunção de Riscos , Consumo de Bebidas Alcoólicas/psicologia , Animais , Hipocampo/fisiologia , Camundongos Knockout , Técnicas de Cultura de Órgãos , Prevalência , Ratos , Ratos Wistar , Receptores de Glutamato Metabotrópico/deficiência , Especificidade da Espécie
5.
Comp Med ; 63(2): 143-55, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23582421

RESUMO

Sporadic iron overload in rats has been reported, but whether it is due to genetic or environmental causes is unknown. In the current study, phenotypic analysis of Hsd:HHCL Wistar rats revealed a low incidence of histologically detected liver iron overload. Here we characterized the pathophysiology of the iron overload and showed that the phenotype is heritable and due to a mutation in a single gene. We identified a single male rat among the 132 screened animals that exhibited predominantly periportal, hepatocellular iron accumulation. This rat expressed low RNA levels of the iron regulatory hormone hepcidin and low protein levels of transferrin receptor 2 (Tfr2), a membrane protein essential for hepcidin expression in humans and mice and mutated in forms of hereditary hemochromatosis. Sequencing of Tfr2 in the iron-overloaded rat revealed a novel Ala679Gly polymorphism in a highly conserved residue. Quantitative trait locus mapping indicated that this polymorphism correlated strongly with serum iron and transferrin saturations in male rats. Expression of the Gly679 variant in tissue culture cell lines revealed decreased steady-state levels of Tfr2. Characterization of iron metabolism in the progeny of polymorphic rats suggested that homozygosity for the Ala679Gly allele leads to a hemochromatosis phenotype. However, we currently cannot exclude the possibility that a polymorphism or mutation in the noncoding region of Tfr2 contributes to the iron-overload phenotype. Hsd:HHCL rats are the first genetic rat model of hereditary hemochromatosis and may prove useful for understanding the molecular mechanisms underlying the regulation of iron metabolism.


Assuntos
Modelos Animais de Doenças , Hemocromatose/genética , Ratos/genética , Receptores da Transferrina/genética , Sequência de Aminoácidos , Animais , Peptídeos Catiônicos Antimicrobianos/metabolismo , Mapeamento Cromossômico , Feminino , Hemocromatose/metabolismo , Hemocromatose/patologia , Hepcidinas , Ferro/metabolismo , Fígado/metabolismo , Masculino , Dados de Sequência Molecular , Fenótipo , Polimorfismo Genético , Locos de Características Quantitativas , RNA/metabolismo , Alinhamento de Sequência
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