RESUMEN
More than 50% of the HIV-1 latent reservoir is maintained by clonal expansion. The clonally expanded HIV-1-infected cells can contribute to persistent nonsuppressible low-level viremia and viral rebound. HIV-1 integration site and proviral genome landscape profiling reveals the clonal expansion dynamics of HIV-1-infected cells. In individuals under long-term suppressive antiretroviral therapy (ART), HIV-1 integration sites are enriched in specific locations in certain cancer-related genes in the same orientation as the host transcription unit. Single-cell transcriptome analysis revealed that HIV-1 drives aberrant cancer-related gene expression through HIV-1-to-host RNA splicing. Furthermore, the HIV-1 promoter dominates over the host gene promoter and drives high levels of cancer-related gene expression. When HIV-1 integrates into cancer-related genes and causes gain of function of oncogenes or loss of function of tumor suppressor genes, HIV-1 insertional mutagenesis drives the proliferation of HIV-1-infected cells and may cause cancer in rare cases. HIV-1-driven aberrant cancer-related gene expression at the integration site can be suppressed by CRISPR-mediated inhibition of the HIV-1 promoter or by HIV-1 suppressing agents. Given that ART does not suppress HIV-1 promoter activity, therapeutic agents that suppress HIV-1 transcription and halt the clonal expansion of HIV-1-infected cells should be explored to block the clonal expansion of the HIV-1 latent reservoir.
Asunto(s)
Infecciones por VIH/virología , VIH-1/fisiología , Integración Viral , Latencia del Virus , Animales , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Proliferación Celular , Modelos Animales de Enfermedad , Genes Supresores de Tumor , Genoma Viral , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Humanos , Mutagénesis Insercional , Oncogenes , Provirus/genética , Transcripción Genética , ViremiaRESUMEN
Human respiratory syncytial virus (HRSV) is an important respiratory pathogens among children between zero-five years old. Host immunity and viral genetic variability are important factors that can make vaccine production difficult. In this work, differences between biological clones of HRSV were detected in clinical samples in the absence and presence of serum collected from children in the convalescent phase of the illness and from their biological mothers. Viral clones were selected by plaque assay in the absence and presence of serum and nucleotide sequences of the G2 and F2 genes of HRSV biological clones were compared. One non-synonymous mutation was found in the F gene (Ile5Asn) in one clone of an HRSV-B sample and one non-synonymous mutation was found in the G gene (Ser291Pro) in four clones of the same HRSV-B sample. Only one of these clones was obtained after treatment with the child's serum. In addition, some synonymous mutations were determined in two clones of the HRSV-A samples. In conclusion, it is possible that minor sequences could be selected by host antibodies contributing to the HRSV evolutionary process, hampering the development of an effective vaccine, since we verify the same codon alteration in absence and presence of human sera in individual clones of BR-85 sample.
Asunto(s)
Óxido de Aluminio/química , Cocos/química , Productos Agrícolas/crecimiento & desarrollo , Frutas/química , Monoterpenos/análisis , Aceites Volátiles/química , Pelargonium/crecimiento & desarrollo , Dióxido de Silicio/química , Productos Agrícolas/química , Productos Agrícolas/economía , Productos Agrícolas/metabolismo , Industria de Procesamiento de Alimentos/economía , Irán , Residuos Industriales/análisis , Residuos Industriales/economía , Monoterpenos/metabolismo , Aceites Volátiles/economía , Aceites Volátiles/aislamiento & purificación , Aceites Volátiles/metabolismo , Pelargonium/química , Pelargonium/metabolismo , Perfumes/química , Perfumes/economía , Perfumes/aislamiento & purificación , Perfumes/metabolismo , Hojas de la Planta/química , Hojas de la Planta/crecimiento & desarrollo , Hojas de la Planta/metabolismo , Silicatos/química , Suelo/química , Terpenos/análisis , Terpenos/metabolismoRESUMEN
HIV-1 causes a chronic infection in humans that is characterized by high plasma viremia, progressive loss of CD4+ T lymphocytes, and severe immunodeficiency resulting in opportunistic disease and AIDS. Viral persistence is mediated in part by the ability of the Nef protein to down-regulate HLA molecules on the infected cell surface, thereby allowing HIV-1 to evade recognition by antiviral CD8+ T lymphocytes. Extensive research has been conducted on Nef to determine protein domains that are required for its immune evasion activities and to identify critical cellular co-factors, and our mechanistic understanding of this process is becoming more complete. This review highlights our current knowledge of Nef-mediated HLA class I down-regulation and places this work in the context of naturally occurring sequence variation in this protein. We argue that efforts to fully understand the critical role of Nef for HIV-1 pathogenesis will require greater analysis of patient-derived sequences to elucidate subtle differences in immune evasion activity that may alter clinical outcome.