RESUMEN

Late complete atrioventricular block (CAVB) is a rare periprocedural complication in the treatment of atrioventricular (AV) nodal re-entrant tachycardia. However, it can necessitate permanent pacemaker implantation. We present a case of late CAVB that developed during the periprocedural period. Its pathogenesis was attributed to the indirect or functional effects on the fast pathway of the AV node due to the presence of paroxysmal supraventricular tachycardia with PR prolongation. Additionally, PR prolongation regressed to within the normal range after curing the late CAVB, and the advanced AV block with treadmill exercise stress test also improved 1:1 AV conduction with time. Periprocedural complications such as bradyarrhythmia may be reversible if late CAVB occurs within a few weeks after ablation. Thus, urgent permanent pacemaker implantation should be carefully considered. Learning objective: Late high-grade atrioventricular (AV) blocks can develop during the periprocedural period even if antegrade slow pathway ablation does not result in a complete AV block. Late high-grade AV block is a relatively rare periprocedural complication. However, it can necessitate permanent pacemaker implantation. Additionally, if a late high-grade AV block develops within a few weeks after ablation, bradyarrhythmia-such as periprocedural complications-may be reversible and indicate that permanent pacemaker implantation should be carefully considered.

RESUMEN

Anti-retroviral therapy (ART) can inhibit HIV proliferation but not achieve virus eradication from HIV-infected individuals. Under ART-based HIV control, virus-specific CD8+ T-cell responses are often reduced. Here, we investigated the impact of therapeutic vaccination inducing virus-specific CD8+ T-cell responses under ART on viral control in a macaque AIDS model. Twelve rhesus macaques received ART from week 12 to 32 after simian immunodeficiency virus (SIV) infection. Six of them were vaccinated with Sendai virus vectors expressing SIV Gag and Vif at weeks 26 and 32, and Gag/Vif-specific CD8+ T-cell responses were enhanced and became predominant. All macaques controlled viremia during ART but showed viremia rebound after ART cessation. Analysis of in vitro CD8+ cell ability to suppress replication of autologous lymphocytes-derived SIVs found augmentation of anti-SIV efficacy of CD8+ cells after vaccination. In the vaccinated animals, the anti-SIV efficacy of CD8+ cells at week 34 was correlated positively with Gag-specific CD8+ T-cell frequencies and inversely with rebound viral loads at week 34. These results indicate that Gag-specific CD8+ T-cell induction by therapeutic vaccination can augment anti-virus efficacy of CD8+ cells, which may be insufficient for functional cure but contribute to more stable viral control under ART.

Asunto(s)

Síndrome de Inmunodeficiencia Adquirida/terapia , Antirretrovirales/farmacología , Linfocitos T CD8-positivos/inmunología , Vacunas contra el SIDAS/administración & dosificación , Síndrome de Inmunodeficiencia Adquirida del Simio/terapia , Síndrome de Inmunodeficiencia Adquirida/inmunología , Síndrome de Inmunodeficiencia Adquirida/virología , Animales , Antirretrovirales/uso terapéutico , Linfocitos T CD8-positivos/efectos de los fármacos , Modelos Animales de Enfermedad , Productos del Gen gag/inmunología , Productos del Gen vif/inmunología , Humanos , Inmunogenicidad Vacunal , Macaca mulatta , Vacunas contra el SIDAS/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/inmunología , Carga Viral/efectos de los fármacos , Carga Viral/inmunología

RESUMEN

Calmodulin-like skin protein (CLSP) is a secreted peptide that is produced by skin keratinocytes and some related epithelial cells. It has previously been shown that CLSP is recruited via the bloodstream into the central nervous system where it likely exerts a neuroprotective effect against toxicity related to Alzheimer's disease (AD) by binding to the heterotrimeric humanin receptor and activating intracellular survival signaling. However, it remains to be elucidated whether secreted CLSP shows a protective effect in the skin tissues. In the current study, using primary keratinocytes treated with hydrogen peroxide (H2 O2 ) or exposed to ultraviolet (UV) irradiation as senescence models of keratinocytes, we addressed whether CLSP affects senescence in skin keratinocytes. We found that CLSP expression was upregulated by H2 O2 or UV in keratinocytes. Furthermore, co-incubation with recombinant CLSP reduced the increase in senescence-associated ß-galactosidase-positivity in keratinocytes that were induced by H2 O2 or UV. These results suggest that CLSP may function as a senescence-suppressing factor in keratinocytes.

Asunto(s)

Proteínas de Unión al Calcio/fisiología , Senescencia Celular/fisiología , Queratinocitos/metabolismo , Envejecimiento de la Piel , Piel/metabolismo , Proteínas de Unión al Calcio/farmacología , Células Cultivadas , Senescencia Celular/efectos de los fármacos , Humanos , Peróxido de Hidrógeno/efectos adversos , Peróxido de Hidrógeno/metabolismo , Proteínas Recombinantes/farmacología , Piel/efectos de la radiación , Rayos Ultravioleta/efectos adversos , beta-Galactosidasa/metabolismo

RESUMEN

Hypoxemia is seen in patients with pulmonary hypertension and hypoxic pulmonary vasoconstriction worsens their clinical condition. However, vasoconstriction is not the only aspect through which hypoxia induces the progression to pulmonary hypertension. Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor responding to hypoxic conditions by regulating hundreds of genes involved in angiogenesis, erythropoiesis, inflammation, and proliferation. We sought to determine the contribution of HIF-1α in myeloid lineage cells to the pulmonary vascular response to chronic exposure to hypoxia. We generated myeloid-specific HIF-1α knockout (MyeHIF1KO) mice by using Cre-lox P system, and exposed them to hypoxic conditions for 3 weeks to induce pulmonary hypertension. Macrophages from MyeHIF1KO and control mice were used for western blotting, RT-qPCR, chemotaxis assay, and ATP assay. MyeHIF1KO mice exposed to hypoxia for 3 weeks exhibited a significant reduction in the right ventricular systolic pressure accompanied by a decrease in the ratio of the right ventricular weight to left ventricular weight, muscularization of the small pulmonary arteries, and infiltration of macrophages into the lung and right ventricle compared with control mice. HIF-1α-deficient peritoneal macrophages showed less migration toward monocyte chemoattractant protein-1 and a decrease in intracellular ATP levels. These results indicate that HIF-1α in macrophages contributes to the progression of pulmonary vascular remodeling and pulmonary hypertension induced by chronic exposure to hypoxic conditions. The inhibition of myeloid-specific HIF-1α may be a novel therapeutic strategy for the treatment of pulmonary hypertension.

Asunto(s)

Hipertensión Pulmonar/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Hipoxia/complicaciones , Células Mieloides/metabolismo , Remodelación Vascular/genética , Adenosina Trifosfato/metabolismo , Animales , Presión Sanguínea/fisiología , Linaje de la Célula , Movimiento Celular/fisiología , Modelos Animales de Enfermedad , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/fisiopatología , Hipoxia/fisiopatología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Macrófagos Peritoneales/metabolismo , Ratones , Ratones Noqueados

RESUMEN

AIM: Dipeptidyl peptidase-4 (DPP-4) inhibitors lower blood glucose levels through inhibition of incretin degradation, which stimulates insulin secretion. Recent studies reported that DPP-4 inhibitors suppressed atherogenesis in apolipoprotein E-knockout (ApoEKO) mice. In this study, we investigated whether teneligliptin, a DPP-4 inhibitor, affects the development of abdominal aortic aneurysms (AAA) in ApoEKO mice. METHODS: ApoEKO mice were fed a high-fat diet (HFD) and infused with angiotensin (Ang) II by osmotic mini pumps for 4 weeks to induce AAA with (DPP-4i group) or without (control group) teneligliptin administered orally from 1 week before HFD and Ang II infusion to the end of the experiment. Confluent rat vascular smooth muscle cells (VSMCs) were serum-starved for 48 hours, then incubated with or without teneligliptin for another 24 hours and stimulated with Ang II. RESULTS: Treatment with teneligliptin significantly reduced the AAA formation rate (30.7% vs. 71.4% vs. control, P＜0.05), aortic dilatation (1.32±0.09 mm vs. 1.76±0.18 mm in the control, P＜0.05) and severity score (0.75±0.28 vs. 1.91±0.4 in the control, P＜0.05). Elastin degradation grade was also attenuated in DPP-4i group (2.83±0.17 vs. 3.45±0.16 in the control, P＜0.05). The number of macrophages infiltrating into the abdominal aorta was decreased in the DPP-4i group (51.8± 29.8/section vs. 219.5±78.5/section in the control, P＜0.05). Teneligliptin attenuated Ang II-induced phosphorylation of extracellular signal-regulated kinase (ERK) and Akt, and mRNA expression of monocyte chemoattractant protein-1 in VSMCs. CONCLUSION: Treatment with teneligliptin suppressed AAA formation in ApoEKO mice with HFD and Ang II infusion. Suppression of macrophage infiltration by teneligliptin may be involved in the inhibition of AAA formation.

Asunto(s)

Aneurisma de la Aorta Abdominal/prevención & control , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Modelos Animales de Enfermedad , Macrófagos/efectos de los fármacos , Pirazoles/farmacología , Tiazolidinas/farmacología , Animales , Células Cultivadas , Macrófagos/citología , Masculino , Ratones , Ratones Noqueados para ApoE

RESUMEN

Hypoxia-inducible factor (HIF)-1α is a transcription factor that regulates various genes responding to hypoxic conditions. We previously reported that myeloid-specific activation of HIF-1α had protective effects on hypertensive cardiovascular remodelling in mice. However the role of myeloid lineage HIF-1α in the development of abdominal aortic aneurysm (AAA) has not been determined. Myeloid-specific HIF-1α knockout (HIF-1KO) mice were created using a Cre-lox recombination system in the background of apolipoprotein E-deficient (ApoE-/-) mice. HIF-1KO and control mice were fed high-fat diet (HFD) and infused with angiotensin II (Ang II, 1800 ng/kg/min) by an osmotic mini pump for 4 weeks to induce AAA formation. Deletion of HIF-1α increased aortic external diameter (2.47±0.21 mm versus 1.80±0.28 mm in control, P=0.035). AAA formation rate (94.4% in HIF-1KO versus 81.8% in control) was not statistically significant. Elastic lamina degradation grade determined by Elastica van Gieson (EVG) staining was deteriorated in HIF-1KO mice (3.91±0.08 versus 3.25±0.31 in control, P=0.013). The number of infiltrated macrophages into the abdominal aorta was increased in HIF-1KO mice. Expression of tissue inhibitors of metalloproteinases (TIMPs) was suppressed in the aorta and peritoneal macrophages (PMs) from HIF-1KO mice compared with control mice. HIF-1α in myeloid lineage cells may have a protective role against AAA formation induced by Ang II and HFD in ApoE-/- mice.

Asunto(s)

Aneurisma de la Aorta Abdominal/fisiopatología , Subunidad alfa del Factor 1 Inducible por Hipoxia/fisiología , Angiotensina II , Animales , Aorta Abdominal/patología , Aneurisma de la Aorta Abdominal/inducido químicamente , Aneurisma de la Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/patología , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/fisiología , Hemodinámica/fisiología , Subunidad alfa del Factor 1 Inducible por Hipoxia/deficiencia , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Macrófagos Peritoneales/metabolismo , Macrófagos Peritoneales/patología , Masculino , Ratones Noqueados , Músculo Liso Vascular/patología , ARN Mensajero/genética , Análisis de Supervivencia , Inhibidores Tisulares de Metaloproteinasas/genética , Inhibidores Tisulares de Metaloproteinasas/metabolismo

RESUMEN

BACKGROUND: In Indonesia, highly pathogenic avian influenza A(H5N1) virus has become endemic in poultry and has caused sporadic deadly infections in human. Since 2012, we have conducted fixed-point surveillance of avian influenza viruses at a live-poultry market in East Java, Indonesia. In this study, we examined the seroprevalence of avian influenza A(H5N1) virus infection among market workers. METHODS: Sera were collected from 101 workers in early 2014 and examined for antibody activity against avian A(H5N1) Eurasian lineage virus by a hemagglutination-inhibition (HI) assay. RESULTS: By the HI assay, 84% of the sera tested positive for antibody activity against the avian virus. Further analysis revealed that the average HI titer in 2014 was 2.9-fold higher than in 2012 and that seroconversion occurred in 44% of paired sera (11 of 25) between 2012 and 2014. A medical history survey was performed in 2016; responses to questionnaires indicated that none of workers had had severe acute respiratory illness during 2013. CONCLUSIONS: This study provides evidence of a high prevalence of avian A(H5N1) virus infection in 2013 among workers at a live-poultry market. However, because no instances of hospitalizations were reported, we can conclude the virus did not manifest any clinical symptoms in workers.

Asunto(s)

Crianza de Animales Domésticos , Anticuerpos Antivirales/sangre , Infecciones Asintomáticas/epidemiología , Subtipo H5N1 del Virus de la Influenza A/inmunología , Gripe Humana/epidemiología , Exposición Profesional , Animales , Pruebas de Inhibición de Hemaglutinación , Humanos , Indonesia/epidemiología , Aves de Corral , Estudios Seroepidemiológicos

Asunto(s)

Aneurisma Falso/diagnóstico por imagen , Angioplastia Coronaria con Balón , Stents , Angioplastia de Balón , Humanos , Hipertensión Pulmonar/complicaciones , Masculino , Persona de Mediana Edad , Arteria Pulmonar , Resultado del Tratamiento

RESUMEN

OBJECTIVE: Activation of vagal nerve suppresses inflammatory responses through activation of α7 nicotinic acetylcholine receptor (nAchR). We sought to determine whether AR-R17779, a selective agonist of α7nAchR, affects the development of abdominal aortic aneurysm (AAA). METHODS AND RESULTS: AAA was induced by topical application of calcium chloride (CaCl2) to abdominal aorta (AAA group). NaCl (0.9%) was substituted for CaCl2 as a sham operation (SHAM group). AR-R17779 was administered in drinking water (AAA/AR-R group). One and 6 weeks after the operation, aortic tissue was excised for histological and molecular analyses. Aortic diameter and macrophage infiltration into the aortic adventitia were increased in AAA group compared with SHAM group at 6 weeks. Treatment with AR-R17779 reduced the diameter of the aorta and macrophage infiltration compared with AAA group. Wavy morphology of the elastic lamellae was lost in AAA group while it was preserved in AAA/AR-R group. Expression of inflammatory cytokines and matrix metalloproteinase (MMP) activities were enhanced in AAA group, which was suppressed in AAA/AR-R group. AR-R17779 treatment suppressed CaCl2-induced expression of cytokines, activities of MMPs and NF-κB activation at 1 week when aortic dilatation had not developed. CONCLUSION: Treatment with AR-R17779 prevented the enlargement of abdominal aorta induced by CaCl2 in association with reduced inflammation and extracellular matrix disruption. These findings suggest therapeutic potential of α7nAchR activation for prevention of AAA development.

Asunto(s)

Aneurisma de la Aorta Abdominal/prevención & control , Hidrocarburos Aromáticos con Puentes/farmacología , Compuestos de Espiro/farmacología , Receptor Nicotínico de Acetilcolina alfa 7/agonistas , Animales , Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Abdominal/metabolismo , Western Blotting , Citocinas/biosíntesis , Citocinas/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Metaloproteinasas de la Matriz/biosíntesis , Metaloproteinasas de la Matriz/genética , Ratones , Ratones Endogámicos C57BL , ARN/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa

RESUMEN

BACKGROUND: Clinical trials have shown that treatment of patients with type 2 diabetes with pioglitazone, a peroxisome proliferator-activated receptor (PPAR)γ agonist, reduces cardiovascular events. However, the effect of PPARγ agonists on endoplasmic reticulum (ER) stress that plays an important role in the progression of atherosclerosis has not been determined. We sought to determine the effect of PPARγ agonists on ER stress induced by palmitate, the most abundant saturated fatty acid in the serum. METHODS AND RESULTS: Protein expression of ER stress marker was evaluated by Western blot analysis and stearoyl-CoA desaturase1 (SCD-1) mRNA expression was evaluated by qRT-PCR. Macrophage apoptosis was detected by flowcytometry. Pioglitazone and rosiglitazone reduced palmitate-induced phosphorylation of PERK, a marker of ER stress, in RAW264.7, a murine macrophage cell line. Pioglitazone also suppressed palmitate-induced apoptosis in association with inhibition of CHOP expression, JNK phosphorylation and cleavage of caspase-3. These effects of pioglitazone were reversed by GW9662, a PPARγ antagonist, indicating that PPARγ is involved in this process. PPARγ agonists increased expression of SCD-1 that introduces a double bond on the acyl chain of long-chain fatty acid. 4-(2-Chlorophenoxy)-N-(3-(3-methylcarbamoyl)phenyl)piperidine-1-carboxamide, an inhibitor of SCD-1, abolished the anti-ER stress and anti-apoptotic effects of pioglitazone. These results suggest that PPARγ agonists attenuate palmitate-induced ER stress and apoptosis through SCD-1 induction. Up-regulation of SCD-1 may contribute to the reduction of cardiovascular events by treatment with PPARγ agonists.

Asunto(s)

Macrófagos/efectos de los fármacos , PPAR gamma/agonistas , Palmitatos/toxicidad , Estearoil-CoA Desaturasa/genética , Tiazolidinedionas/farmacología , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Estrés del Retículo Endoplásmico/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Pioglitazona , Rosiglitazona , Estearoil-CoA Desaturasa/metabolismo , Regulación hacia Arriba

RESUMEN

BACKGROUND: Hepatitis C virus (HCV) is a major global health problem, causing chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Development of well-tolerated regimens with high cure rates and fewer side effects is still much needed. Recently, natural antimicrobial peptides (AMPs) are attracting more attention as biological compounds and can be a good template to develop therapeutic agents, including antiviral agents against a variety of viruses. Various AMPs have been characterized from the venom of different venomous animals including scorpions. METHODS: The possible antiviral activities of crude venoms obtained from five Egyptian scorpion species (Leiurus quinquestriatus, Androctonus amoreuxi, A. australis, A. bicolor and Scorpio maurus palmatus) were evaluated by a cell culture method using Huh7.5 cells and the J6/JFH1-P47 strain of HCV. Time-of-addition experiments and inactivation of enzymatic activities of the venoms were carried out to determine the characteristics of the anti-HCV activities. RESULTS: S. maurus palmatus and A. australis venoms showed anti-HCV activities, with 50% inhibitory concentrations (IC50) being 6.3 ± 1.6 and 88.3 ± 5.8 µg/ml, respectively. S. maurus palmatus venom (30 µg/ml) impaired HCV infectivity in culture medium, but not inside the cells, through virocidal effect. The anti-HCV activity of this venom was not inhibited by a metalloprotease inhibitor or heating at 60°C. The antiviral activity was directed preferentially against HCV. CONCLUSIONS: S. maurus palmatus venom is considered as a good natural source for characterization and development of novel anti-HCV agents targeting the entry step. To our knowledge, this is the first report describing antiviral activities of Egyptian scorpion venoms against HCV, and may open a new approach towards discovering antiviral compounds derived from scorpion venoms.

Asunto(s)

Antivirales/toxicidad , Hepacivirus/efectos de los fármacos , Hepatitis C/virología , Venenos de Escorpión/toxicidad , Animales , Hepacivirus/fisiología , Humanos , Escorpiones/química

RESUMEN

In the present study we sought to determine the effect of CoCl2, an inhibitor of PHD (prolyl hydroxylase domain protein), on the development of AAA (abdominal aortic aneurysm). AAA was induced in C57BL/6 mice by periaortic application of CaCl2 (AAA group). NaCl (0.9%)-treated mice were used as a sham control (SHAM group). Mice were treated with 0.05% CoCl2 in the drinking water (AAA/CoCl2 group). At 1 and 6 weeks after the operation, aortic tissue was excised for further examination. After 6 weeks of CaCl2 treatment, aortic diameter and macrophage infiltration into the aortic adventitia were increased in the AAA group compared with the SHAM group. Treatment with CoCl2 reduced the aneurysmal size and macrophage infiltration compared with the AAA group. Aortic expression of inflammatory cytokines and MCP-1 (monocyte chemoattractant protein-1) and the activities of MMP-9 (matrix metalloproteinase-9) and MMP-2 were enhanced in the AAA group and attenuated in the AAA/CoCl2 group. Expression of cytokines and the activities of MMPs were already increased after 1 week of CaCl2 treatment, but were suppressed by CoCl2 treatment in association with reduced NF-κB (nuclear factor κB) phosphorylation. Treatment with CoCl2 in mice prevented the development of CaCl2-induced AAA in association with reduced inflammation and ECM (extracellular matrix) disruption. The results of the present study suggest that PHD plays a critical role in the development of AAA and that there is a therapeutic potential for PHD inhibitors in the prevention of AAA development.

Asunto(s)

Aorta Abdominal/efectos de los fármacos , Aneurisma de la Aorta Abdominal/prevención & control , Aortitis/prevención & control , Cobalto/farmacología , Inhibidores Enzimáticos/farmacología , Matriz Extracelular/metabolismo , Prolina Dioxigenasas del Factor Inducible por Hipoxia/antagonistas & inhibidores , Animales , Aorta Abdominal/enzimología , Aorta Abdominal/inmunología , Aorta Abdominal/patología , Aneurisma de la Aorta Abdominal/inducido químicamente , Aneurisma de la Aorta Abdominal/enzimología , Aneurisma de la Aorta Abdominal/inmunología , Aneurisma de la Aorta Abdominal/patología , Aortitis/inducido químicamente , Aortitis/enzimología , Aortitis/inmunología , Aortitis/patología , Cloruro de Calcio , Catalasa/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Mediadores de Inflamación/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Fosforilación , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1 , Factores de Tiempo , Factor de Transcripción ReIA/metabolismo

RESUMEN

Several major histocompatibility complex class I (MHC-I) alleles are associated with lower viral loads and slower disease progression in human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections. Immune-correlates analyses in these MHC-I-related HIV/SIV controllers would lead to elucidation of the mechanism for viral control. Viral control associated with some protective MHC-I alleles is attributed to CD8+ T-cell responses targeting Gag epitopes. We have been trying to know the mechanism of SIV control in multiple groups of Burmese rhesus macaques sharing MHC-I genotypes at the haplotype level. Here, we found a protective MHC-I haplotype, 90-010-Id (D), which is not associated with dominant Gag-specific CD8+ T-cell responses. Viral loads in five D+ animals became significantly lower than those in our previous cohorts after 6 months. Most D+ animals showed predominant Nef-specific but not Gag-specific CD8+ T-cell responses after SIV challenge. Further analyses suggested two Nef-epitope-specific CD8+ T-cell responses exerting strong suppressive pressure on SIV replication. Another set of five D+ animals that received a prophylactic vaccine using a Gag-expressing Sendai virus vector showed significantly reduced viral loads compared to unvaccinated D+ animals at 3 months, suggesting rapid SIV control by Gag-specific CD8+ T-cell responses in addition to Nef-specific ones. These results present a pattern of SIV control with involvement of non-Gag antigen-specific CD8+ T-cell responses.

Asunto(s)

Linfocitos T CD8-positivos/inmunología , Haplotipos/genética , Complejo Mayor de Histocompatibilidad/genética , Virus de la Inmunodeficiencia de los Simios/genética , Virus de la Inmunodeficiencia de los Simios/inmunología , Animales , Genoma Viral/genética , Macaca mulatta , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/patogenicidad

RESUMEN

Induction of durable cellular immune responses by vaccination is an important strategy for the control of persistent pathogen infection. Viral vectors are promising vaccine tools for eliciting antigen-specific T-cell responses. Repeated vaccination may contribute to durable memory T-cell induction, but anti-vector antibodies could be an obstacle to its efficacy. We previously developed a Sendai virus (SeV) vector vaccine and showed the potential of this vector for efficient T-cell induction in macaques. Here, we examined whether repeated SeV vector vaccination with short intervals can enhance antigen-specific CD8(+) T-cell responses. Four rhesus macaques possessing the MHC-I haplotype 90-120-Ia were immunized three times with intervals of three weeks. For the vaccination, we used replication-defective F-deleted SeV vectors inducing CD8(+) T-cell responses specific for simian immunodeficiency virus Gag(206-216) and Gag(241-249), which are dominant epitopes restricted by 90-120-Ia-derived MHC-I molecules. All four animals showed higher Gag(206-216)-specific and Gag(241-249)-specific CD8(+) T-cell responses after the third vaccination than those after the first vaccination, indicating enhancement of antigen-specific CD8(+) T-cell responses by the second/third SeV vector vaccination even with short intervals. These results suggest that repeated SeV vector vaccination can contribute to induction of efficient and durable T-cell responses.

Asunto(s)

Linfocitos T CD8-positivos/inmunología , Productos del Gen gag/inmunología , Vectores Genéticos , Vacunas contra el SIDAS/administración & dosificación , Virus Sendai , Virus de la Inmunodeficiencia de los Simios/inmunología , Animales , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Antígenos Virales/genética , Antígenos Virales/inmunología , Productos del Gen gag/genética , Vectores Genéticos/administración & dosificación , Vectores Genéticos/inmunología , Inmunización Secundaria , Macaca mulatta , Proteínas Recombinantes de Fusión , Vacunas contra el SIDAS/genética , Vacunas contra el SIDAS/inmunología , Virus Sendai/genética , Virus Sendai/inmunología , Virus de la Inmunodeficiencia de los Simios/genética , Factores de Tiempo , Vacunación

RESUMEN

Viral vectors are promising vaccine tools for eliciting potent cellular immune responses. Pre-existing anti-vector antibodies, however, can be an obstacle to their clinical use in humans. We previously developed a Sendai virus (SeV) vector vaccine and showed the potential of this vector for efficient CD8(+) T-cell induction in macaques. Here, we investigated the immunogenicity of SeV vector vaccination in the presence of anti-SeV antibodies. We compared antigen-specific CD8(+) T-cell responses after intranasal or intramuscular immunization with a lower dose (one-tenth of that in our previous studies) of SeV vector expressing simian immunodeficiency virus Gag antigen (SeV-Gag) between naive and pre-SeV-infected cynomolgus macaques. Intranasal SeV-Gag immunization efficiently elicited Gag-specific CD8(+) T-cell responses not only in naive but also in pre-SeV-infected animals. In contrast, intramuscular SeV-Gag immunization induced Gag-specific CD8(+) T-cell responses efficiently in naive but not in pre-SeV-infected animals. These results indicate that both intranasal and intramuscular SeV administrations are equivalently immunogenic in the absence of anti-SeV antibodies, whereas intranasal SeV vaccination is more immunogenic than intramuscular in the presence of anti-SeV antibodies. It is inferred from a recent report investigating the prevalence of anti-SeV antibodies in humans that SeV-specific neutralizing titers in more than 70% of people are no more than those at the SeV-Gag vaccination in pre-SeV-infected macaques in the present study. Taken together, this study implies the potential of intranasal SeV vector vaccination to induce CD8(+) T-cell responses even in humans, suggesting a rationale for proceeding to a vaccine clinical trial using this vector.

Asunto(s)

Portadores de Fármacos/administración & dosificación , Vectores Genéticos/administración & dosificación , Vacunas contra el SIDAS/administración & dosificación , Vacunas contra el SIDAS/inmunología , Administración Intranasal , Animales , Linfocitos T CD8-positivos/inmunología , Productos del Gen gag/genética , Productos del Gen gag/inmunología , Vectores Genéticos/inmunología , Inyecciones Intramusculares , Macaca , Vacunas contra el SIDAS/genética , Virus Sendai/genética , Virus Sendai/inmunología , Virus de la Inmunodeficiencia de los Simios/genética , Virus de la Inmunodeficiencia de los Simios/inmunología

RESUMEN

Major histocompatibility complex class I (MHC-I)-restricted CD8(+) cytotoxic T lymphocyte (CTL) responses are crucial for the control of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication. In particular, Gag-specific CTL responses have been shown to exert strong suppressive pressure on HIV/SIV replication. Additionally, association of Vif-specific CTL frequencies with in vitro anti-SIV efficacy has been suggested recently. Host MHC-I genotypes could affect the immunodominance patterns of these potent CTL responses. Here, Gag- and Vif-specific CTL responses during primary SIVmac239 infection were examined in three groups of Burmese rhesus macaques, each group having a different MHC-I haplotype. The first group of four macaques, which possessed the MHC-I haplotype 90-010-Ie, did not show Gag- or Vif-specific CTL responses. However, Nef-specific CTL responses were elicited, suggesting that primary SIV infection does not induce predominant CTL responses specific for Gag/Vif epitopes restricted by 90-010-Ie-derived MHC-I molecules. In contrast, Gag- and Vif-specific CTL responses were induced in the second group of two 89-075-Iw-positive animals and the third group of two 91-010-Is-positive animals. Considering the potential of prophylactic vaccination to affect CTL immunodominance post-viral exposure, these groups of macaques would be useful for evaluation of vaccine antigen-specific CTL efficacy against SIV infection.

Asunto(s)

Linfocitos T CD8-positivos/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Virus de la Inmunodeficiencia de los Simios/inmunología , Linfocitos T Citotóxicos/inmunología , Animales , Productos del Gen gag/inmunología , Productos del Gen vif/inmunología , Haplotipos , Antígenos de Histocompatibilidad Clase I/genética , Macaca mulatta

RESUMEN

Cytotoxic T lymphocyte (CTL) responses are crucial for the control of human and simian immunodeficiency virus (HIV and SIV) replication. A promising AIDS vaccine strategy is to induce CTL memory resulting in more effective CTL responses post-viral exposure compared to those in natural HIV infections. We previously developed a CTL-inducing vaccine and showed SIV control in some vaccinated rhesus macaques. These vaccine-based SIV controllers elicited vaccine antigen-specific CTL responses dominantly in the acute phase post-challenge. Here, we examined CTL responses post-challenge in those vaccinated animals that failed to control SIV replication. Unvaccinated rhesus macaques possessing the major histocompatibility complex class I haplotype 90-088-Ij dominantly elicited SIV non-Gag antigen-specific CTL responses after SIV challenge, while those induced with Gag-specific CTL memory by prophylactic vaccination failed to control SIV replication with dominant Gag-specific CTL responses in the acute phase, indicating dominant induction of vaccine antigen-specific CTL responses post-challenge even in non-controllers. Further analysis suggested that prophylactic vaccination results in dominant induction of vaccine antigen-specific CTL responses post-viral exposure but delays SIV non-vaccine antigen-specific CTL responses. These results imply a significant influence of prophylactic vaccination on CTL immunodominance post-viral exposure, providing insights into antigen design in development of a CTL-inducing AIDS vaccine.

Asunto(s)

Vacunas contra el SIDA/inmunología , Antígenos Virales/inmunología , Vacunas contra el SIDAS/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Virus de la Inmunodeficiencia de los Simios/inmunología , Linfocitos T Citotóxicos/inmunología , Vacunas contra el SIDA/uso terapéutico , Síndrome de Inmunodeficiencia Adquirida/prevención & control , Animales , Humanos , Macaca mulatta , Vacunas contra el SIDAS/uso terapéutico , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología

RESUMEN

A novel 2-step synthesis of oxazole-4-carboxylates from aldehydes was developed, which is characterized by the utilization of 3-oxazoline-4-carboxylates as synthetic intermediates. The facile preparation of 4-keto-oxazole derivatives from 3-oxazoline-4-carboxylates based on their interesting reactivity toward Grignard reagents is also described.

Asunto(s)

Aldehídos/química , Ácidos Carboxílicos/síntesis química , Cetonas/síntesis química , Oxazoles/síntesis química , Ácidos Carboxílicos/química , Técnicas Químicas Combinatorias , Indicadores y Reactivos , Cetonas/química , Estructura Molecular , Oxazoles/química

RESUMEN

C(3)-symmetric chiral trisimidazoline was designed and synthesized as a new entry of organocatalyst with the concept of constructing C(3)-symmetric molecules with three C(2)-symmetric chiral components, and the application of this novel catalyst to asymmetric conjugate addition of beta-ketoesters to nitroolefins was described.

Asunto(s)

Diseño de Fármacos , Imidazolinas/química , Alquenos/química , Catálisis , Ésteres/química , Estereoisomerismo , Especificidad por Sustrato

RESUMEN

3Beta,4beta:15,16-diepoxy-13(16),14-clerodadiene (1) and a new clerodane diterpenoid designated thysaspathone (2) were isolated from the liverwort Thysananthus spathulistipus, while Radula appressa produced radulannin A (3), radulannin L (4), 2-geranyl-3,5-dihydroxybibenzyl (5), 2(S)-2-methyl-2-(4-methyl-3-pentenyl)-7-hydroxy-5-(2-phenylethyl) chromene (o-cannabichromene) (6), 6-hydroxy-4-(2-phenylethyl) benzofuran (7), and o-cannabicyclol (8). All of the isolated compounds inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and the greatest inhibition was attributed to compound 5, with an IC50 value of 4.5 microM.

Asunto(s)

Bibencilos/química , Diterpenos de Tipo Clerodano/química , Hepatophyta/química , Neopreno/química , Óxido Nítrico/antagonistas & inhibidores , Animales , Bibencilos/farmacología , Línea Celular , Células Cultivadas , Diterpenos de Tipo Clerodano/farmacología , Evaluación Preclínica de Medicamentos , Concentración 50 Inhibidora , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Estructura Molecular , Neopreno/farmacología , Óxido Nítrico/química