RESUMO
Human pegivirus (HPgV)-formerly known as GB virus C and hepatitis G virus-is a poorly characterized RNA virus that infects about one-sixth of the global human population and is transmitted frequently in the blood supply. We create an animal model of HPgV infection by infecting macaque monkeys with a new simian pegivirus (SPgV) discovered in wild baboons. Using this model, we provide a high-resolution, longitudinal picture of SPgV viremia where the dose, route, and timing of infection are known. We detail the highly variable acute phase of SPgV infection, showing that the viral load trajectory early in infection is dependent on the infecting dose, whereas the chronic-phase viremic set point is not. We also show that SPgV has an extremely low propensity for accumulating sequence variation, with no consensus-level variants detected during the acute phase of infection and an average of only 1.5 variants generated per 100 infection-days. Finally, we show that SPgV RNA is highly concentrated in only two tissues: spleen and bone marrow, with bone marrow likely producing most of the virus detected in plasma. Together, these results reconcile several paradoxical observations from cross-sectional analyses of HPgV in humans and provide an animal model for studying pegivirus biology.
Assuntos
Medula Óssea/virologia , Modelos Animais de Doenças , Infecções por Flaviviridae/complicações , Vírus GB C , Tropismo Viral , Síndrome da Imunodeficiência Adquirida/prevenção & controle , Animais , Medula Óssea/patologia , Evolução Molecular , Feminino , Variação Genética , Infecções por HIV/virologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Funções Verossimilhança , Macaca , Masculino , Papio , Filogenia , RNA Viral/sangue , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Carga Viral , ViremiaRESUMO
The expression of endogenous retrotransposable elements, including long interspersed nuclear element 1 (LINE-1 or L1) and human endogenous retrovirus, accompanies neoplastic transformation and infection with viruses such as HIV. The ability to engender immunity safely against such self-antigens would facilitate the development of novel vaccines and immunotherapies. In this article, we address the safety and immunogenicity of vaccination with these elements. We used immunohistochemical analysis and literature precedent to identify potential off-target tissues in humans and establish their translatability in preclinical species to guide safety assessments. Immunization of mice with murine L1 open reading frame 2 induced strong CD8 T cell responses without detectable tissue damage. Similarly, immunization of rhesus macaques with human LINE-1 open reading frame 2 (96% identity with macaque), as well as simian endogenous retrovirus-K Gag and Env, induced polyfunctional T cell responses to all Ags, and Ab responses to simian endogenous retrovirus-K Env. There were no adverse safety or pathological findings related to vaccination. These studies provide the first evidence, to our knowledge, that immune responses can be induced safely against this class of self-antigens and pave the way for investigation of them as HIV- or tumor-associated targets.
Assuntos
Vacinas contra a AIDS/administração & dosagem , Vacinas contra a AIDS/imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Elementos de DNA Transponíveis/imunologia , Retrovirus Endógenos/imunologia , Vacinas contra a AIDS/genética , Adulto , Sequência de Aminoácidos , Animais , Vacinas Anticâncer/genética , Elementos de DNA Transponíveis/genética , Modelos Animais de Doenças , Retrovirus Endógenos/genética , Retrovirus Endógenos/metabolismo , Feminino , Humanos , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologiaRESUMO
Accurate detection of West Nile virus (WNV) in corvids is essential for monitoring the spread of virus during the mosquito season. Viremia in corvids is very high, with titers approaching 10(8) viral particles/ml. In the presence of such marked viremia, the sensitivity of real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis is unnecessary, and more cost-effective methods should be assessed. To this end, antigen-capture ELISA (ACE) and immunohistochemical (IHC) assays were evaluated. Skin, cloacal swab specimens, and feathers from corvids were tested by use of ACE, and results were compared with results obtained from use of real-time RT-PCR analysis. Of the 3 sample types, skin gave the best sensitivity (98%) and specificity (100%). Skin, brain, kidney, and spleen from corvids were analyzed by IHC, and results were compared with real-time RT-PCR results. Kidney and spleen were more often positive by use of IHC than were brain and skin tissue; however, IHC did not perform as well as ACE in the identification of virus-positive birds. Results of this study support the use of a skin sample in an ACE format as an effective surveillance method for corvids.
Assuntos
Doenças das Aves/diagnóstico , Corvos , Ensaio de Imunoadsorção Enzimática/veterinária , Imuno-Histoquímica/veterinária , Febre do Nilo Ocidental/veterinária , Vírus do Nilo Ocidental/isolamento & purificação , Animais , Antígenos Virais/análise , Doenças das Aves/virologia , Encéfalo/virologia , Cloaca/virologia , Análise Custo-Benefício , Ensaio de Imunoadsorção Enzimática/economia , Ensaio de Imunoadsorção Enzimática/métodos , Plumas/virologia , Imuno-Histoquímica/economia , Imuno-Histoquímica/métodos , Rim/virologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa/economia , Reação em Cadeia da Polimerase Via Transcriptase Reversa/veterinária , Pele/virologia , Baço/virologia , Febre do Nilo Ocidental/diagnóstico , Febre do Nilo Ocidental/virologia , Vírus do Nilo Ocidental/genética , Vírus do Nilo Ocidental/imunologiaRESUMO
Three White-tailed Deer shot within 5 km during the 2001 hunting season in Wisconsin tested positive for chronic wasting disease, a prion disease of cervids. Subsequent sampling within 18 km showed a 3% prevalence (n=476). This discovery represents an important range extension for chronic wasting disease into the eastern United States.