RESUMEN
Numerous challenges have impeded HIV-1 vaccine development. Among these is the lack of a convenient small animal model in which to study antibody elicitation and efficacy. We describe a chimeric Rhabdo-Immunodeficiency virus (RhIV) murine model that recapitulates key features of HIV-1 entry, tropism and antibody sensitivity. RhIVs are based on vesicular stomatitis viruses (VSV), but viral entry is mediated by HIV-1 Env proteins from diverse HIV-1 strains. RhIV infection of transgenic mice expressing human CD4 and CCR5, exclusively on mouse CD4+ cells, at levels mimicking those on human CD4+ T-cells, resulted in acute, resolving viremia and CD4+ T-cell depletion. RhIV infection elicited protective immunity, and antibodies to HIV-1 Env that were primarily non-neutralizing and had modest protective efficacy following passive transfer. The RhIV model enables the convenient in vivo study of HIV-1 Env-receptor interactions, antiviral activity of antibodies and humoral responses against HIV-1 Env, in a genetically manipulatable host.
Asunto(s)
Anticuerpos Antivirales/biosíntesis , Linfocitos T CD4-Positivos/inmunología , VIH-1/genética , Virus Reordenados/genética , Vesiculovirus/genética , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética , Animales , Especificidad de Anticuerpos , Antígenos CD4/genética , Antígenos CD4/inmunología , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/virología , Modelos Animales de Enfermedad , Efecto Fundador , Expresión Génica , Infecciones por VIH/genética , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/inmunología , Humanos , Ratones , Ratones Transgénicos , Virus Reordenados/inmunología , Receptores CCR5/genética , Receptores CCR5/inmunología , Vesiculovirus/inmunología , Tropismo Viral/genética , Tropismo Viral/inmunología , Internalización del Virus , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunologíaRESUMEN
GWAS have identified hundreds of height-associated loci. However, determining causal mechanisms is challenging, especially since height-relevant tissues (e.g. growth plates) are difficult to study. To uncover mechanisms by which height GWAS variants function, we performed epigenetic profiling of murine femoral growth plates. The profiled open chromatin regions recapitulate known chondrocyte and skeletal biology, are enriched at height GWAS loci, particularly near differentially expressed growth plate genes, and enriched for binding motifs of transcription factors with roles in chondrocyte biology. At specific loci, our analyses identified compelling mechanisms for GWAS variants. For example, at CHSY1, we identified a candidate causal variant (rs9920291) overlapping an open chromatin region. Reporter assays demonstrated that rs9920291 shows allelic regulatory activity, and CRISPR/Cas9 targeting of human chondrocytes demonstrates that the region regulates CHSY1 expression. Thus, integrating biologically relevant epigenetic information (here, from growth plates) with genetic association results can identify biological mechanisms important for human growth.