Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Neutralizantes/uso terapéutico , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Virus de la Inmunodeficiencia de los Simios/inmunología , Animales , Animales Recién Nacidos , Modelos Animales de Enfermedad , VIH-1/inmunología , Humanos , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Carga ViralAsunto(s)
Humanos , Animales , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Virus de la Inmunodeficiencia de los Simios/inmunología , Anticuerpos Neutralizantes/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , VIH-1/inmunología , Carga Viral , Modelos Animales de Enfermedad , Animales Recién NacidosRESUMEN
The goal of this study was to morphologically characterize a ligated ileal loop model of Salmonella enterica serotype Typhimurium infection in rhesus macaques (Macaca mulatta) and to verify the occurrence of Salmonella-induced cell death in vivo. Eight adult healthy male rhesus macaques were used for ligated ileal loop surgery. Four macaques had been intravenously inoculated with simian immunodeficiency virus (SIV) mac251. Ileal ligated loops were inoculated with wild-type (WT) S. Typhimurium strain IR715 (ATCC14028 nal (r)), an isogenic noninvasive mutant strain (ATCC14028 nal (r) ΔsipAΔsopABDE2), or sterile Luria Bertani broth. Loops were surgically removed at 2, 5, and 8 hours post-inoculation (hpi). Intestinal samples were processed for histopathology, immunohistochemistry for detecting Salmonella, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL), and transmission electron microscopy. Combined histopathology scores were similar between SIV-infected and control macaques. As expected, the invasion-deficient mutant was less pathogenic than WT S. Typhimurium. Neutrophil infiltrate in the intestinal mucosa correlated with bacterial loads (r = 0.7148; P < .0001) and fluid accumulation (r = 0.6019; P < .0001) in the lumen of the intestinal loops. Immunolabeled WT S. Typhimurium was observed in the epithelium and lamina propria at the tip of the villi at 2 hpi, progressing toward deeper lamina propria at 5-8 hpi. Most TUNEL-positive cells localized to the lamina propria, and some had morphological features of macrophages. Ultrastructurally, bacteria were observed intracellularly in the lamina propria as well as within apoptotic bodies. This study provides morphological evidence of Salmonella-induced cell death in vivo in a relevant nonhuman primate model.
Asunto(s)
Enfermedades Intestinales/veterinaria , Macaca mulatta , Enfermedades de los Monos/microbiología , Salmonelosis Animal/patología , Salmonella typhimurium/aislamiento & purificación , Síndrome de Inmunodeficiencia Adquirida del Simio/patología , Virus de la Inmunodeficiencia de los Simios/aislamiento & purificación , Animales , Modelos Animales de Enfermedad , Inmunohistoquímica/veterinaria , Etiquetado Corte-Fin in Situ/veterinaria , Enfermedades Intestinales/inmunología , Enfermedades Intestinales/microbiología , Enfermedades Intestinales/virología , Mucosa Intestinal/microbiología , Mucosa Intestinal/ultraestructura , Mucosa Intestinal/virología , Masculino , Microscopía Electrónica de Transmisión/veterinaria , Enfermedades de los Monos/inmunología , Enfermedades de los Monos/patología , Enfermedades de los Monos/virología , Salmonelosis Animal/inmunología , Salmonelosis Animal/microbiología , Salmonelosis Animal/virología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/microbiología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Estadísticas no ParamétricasRESUMEN
Six morphine-exposed and 3 control male Indian rhesus macaques were intravenously inoculated with mixture of SHIV(KU), SHIV(89.6)P and SIV/17E-Fr. These animals were followed for a period of 56 weeks in order to determine CD4 and CD8 profile, viral loads in plasma and cerebrospinal fluid (CSF), relative distribution of 3 pathogenic viruses in blood and brain, binding as well neutralizing antibody levels and cellular immune responses. Both morphine-exposed and control macaques showed a precipitous loss of CD4+ T cells; control animals, however, showed a greater tendency to recover these cells than did their morphine-exposed counterparts. The plasma and CSF viral loads were significantly higher in morphine-exposed group than those in the control group. Four morphine-exposed animals succumbed to SIV/SHIV-induced AIDS at week 18, 19, 20 and 51; post-infection with neurological disorders was found in 3 of the 4 animals. At the end of the 56-week observation period, 2 morphine-exposed and 3 control animals were still alive. All 3 viruses replicated in the blood of both morphine-exposed and control macaques, but the cerebral compartment showed a selection phenomenon; only SIV/17E-Fr and SHIV(KU) successfully crossed the blood brain barrier (BBB). The morphine-exposed macaques further favored viral migration through the blood brain barrier (BBB). SIV/17E-Fr crossed the BBB within 2 weeks in both morphine-exposed and control macaques, whereas SHIV(KU) crossed the BBB more rapidly in morphine-exposed than in control macaques. Three morphine-exposed macaques (euthanized at weeks 18, 19 and 20) did not develop cellular or humoral immune responses, whereas the other 3 morphine-exposed and 3 control macaques developed both cellular and humoral immune responses.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/virología , Morfina/efectos adversos , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/fisiología , Telencéfalo/virología , Replicación Viral/efectos de los fármacos , Síndrome de Inmunodeficiencia Adquirida/inmunología , Animales , Anticuerpos Antivirales , Recuento de Linfocito CD4 , Relación CD4-CD8 , Líquido Cefalorraquídeo/virología , Modelos Animales de Enfermedad , Inmunidad Celular , Macaca mulatta , Masculino , ARN Viral/sangre , ARN Viral/líquido cefalorraquídeo , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Carga ViralRESUMEN
Dendritic cells (DCs) are potent antigen-presenting cells that likely play multiple roles in human immunodeficiency virus type 1 (HIV-1) pathogenesis. We used the simian immunodeficiency virus (SIV)/macaque model to study the effects of infection on homeostatic chemokine expression and DC localization directly in secondary lymphoid tissues. SIV infection altered the expression of chemokines (CCL19/MIP-3beta, CCL21/ 6Ckine, and CCL20/MIP-3alpha) and of chemokine receptors (CCR7 and CCR6) that drive DC trafficking. CCL19/MIP-3beta, CCL20/MIP-3alpha, CCR6, and CCR7 expression increased in lymph nodes during the early systemic burst of viral replication (acute infection), whereas CCL21/6Ckine expression progressively decreased throughout disease to AIDS. Parallel with the SIV-induced perturbations in chemokine expression were changes in the expression of the DC-associated markers, DC-SIGN, DC-LAMP, and DECTIN-1. During AIDS, DC-LAMP mRNA expression levels were significantly reduced in lymph nodes and spleen, and DC-SIGN levels were significantly reduced in spleen. These findings suggest that the disruption of homeostatic chemokine expression is responsible, in part, for alterations in the networks of antigen-presenting cells in lymphoid tissues, ultimately contributing to systemic immunodeficiency.