RESUMEN
Worldwide, prostate cancer (PCa) remains a leading cause of death in men. Histologically, the majority of PCa cases are classified as adenocarcinomas, which are mainly composed of androgen receptor-positive luminal cells. PCa is initially driven by the androgen receptor axis, where androgen-mediated activation of the receptor is one of the primary culprits for disease progression. Therefore, in advanced stage PCa, patients are generally treated with androgen deprivation therapies alone or in combination with androgen receptor pathway inhibitors. However, after an initial decrease, the cancer recurs for majority patients. At this stage, cancer is known as castration-resistant prostate cancer (CRPC). Majority of CRPC tumors still depend on androgen receptor axis for its progression to metastasis. However, in around 20-30% of cases, CRPC progresses via an androgen receptor-independent pathway and is often presented as neuroendocrine cancer (NE). This NE phenotype is highly aggressive with poor overall survival as compared to CRPC adenocarcinoma. NE cancers are resistant to standard taxane chemotherapies, which are often used to treat metastatic disease. Pathologically and morphologically, NE cancers are highly diverse and often co-exist with adenocarcinoma. Due to the lack of proper biomarkers, it is often difficult to make an early diagnosis of this lethal disease. Moreover, increased tumor heterogeneity and admixtures of adeno and NE subtypes in the same tumor make early detection of NE tumors very difficult. With the advancement of our knowledge and sequencing technology, we are now able to better understand the molecular mediators of this transformation pathway. This current study will give an update on how various molecular regulators are involved in these lineage transformation processes and what challenges we are still facing to detect and treat this cancer.
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Tumores Neuroendocrinos , Humanos , Masculino , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/metabolismo , Tumores Neuroendocrinos/genética , Receptores Androgénicos/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Animales , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/genética , Regulación Neoplásica de la Expresión GénicaRESUMEN
We present a longitudinal description of a man with the TARDBP I383V variant of frontotemporal dementia (FTD). His progressive changes in behavior and language resulted in a diagnosis of the right temporal variant of FTD, also called the semantic behavioral variant (sbvFTD). We also present data from a small series of patients with the TARDBP I383V variant who were enrolled in a nationwide FTD research collaboration (ALLFTD). These data support slowly progressive loss of semantic function. While semantic dementia is infrequently considered genetic, the TARDBP I383V variant seems to be an exception. Longitudinal analyses in larger samples are warranted.
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Proteínas de Unión al ADN , Progresión de la Enfermedad , Demencia Frontotemporal , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Unión al ADN/genética , Demencia Frontotemporal/genética , Demencia Frontotemporal/patología , Demencia Frontotemporal/fisiopatología , Estudios LongitudinalesRESUMEN
OBJECTIVE: The paucity of longitudinal natural history studies in MPZ neuropathy remains a barrier to clinical trials. We have completed a longitudinal natural history study in patients with MPZ neuropathies across 13 sites of the Inherited Neuropathies Consortium. METHODS: Change in Charcot-Marie-Tooth Examination Score (CMTES) and Rasch modified CMTES (CMTES-R) were evaluated using longitudinal regression over a 5-year period in subjects with MPZ neuropathy. Data from 139 patients with MPZ neuropathy were examined. RESULTS: The average baseline CMTES and CMTES-R were 10.84 (standard deviation [SD] = 6.0, range = 0-28) and 14.60 (SD = 7.56, range = 0-32), respectively. A mixed regression model showed significant change in CMTES at years 2-5 (mean change from baseline of 0.87 points at 2 years, p = 0.008). Subgroup analysis revealed greater change in CMTES at 2 years in subjects with axonal as compared to demyelinating neuropathy (mean change of 1.30 points [p = 0.016] vs 0.06 points [p = 0.889]). Patients with a moderate baseline neuropathy severity also showed more notable change, by estimate, than those with mild or severe neuropathy (mean 2-year change of 1.14 for baseline CMTES 8-14 [p = 0.025] vs -0.03 for baseline CMTES 0-7 [p = 0.958] and 0.25 for baseline CMTES ≥ 15 [p = 0.6897]). The progression in patients harboring specific MPZ mutations was highly variable. INTERPRETATION: CMTES is sensitive to change over time in adult patients with axonal but not demyelinating forms of MPZ neuropathy. Change in CMTES was greatest in patients with moderate baseline disease severity. These findings will inform future clinical trials of MPZ neuropathies. ANN NEUROL 2023;93:563-576.
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Enfermedad de Charcot-Marie-Tooth , Adulto , Humanos , Enfermedad de Charcot-Marie-Tooth/genética , Estudios Longitudinales , Proteína P0 de la Mielina/genética , Mutación , Progresión de la EnfermedadRESUMEN
Seminary students remain unstudied in the research literature despite their eminent role in caring for the wellbeing of congregants. This study aimed to conduct baseline analysis of their family of origin health, psychological health, and physiological heath by utilizing the Biobehavioral Family Model (BBFM) as a conceptual framework for understanding the associations between these constructs. Statistical analysis utilizing structural equation modeling provided support that the BBFM was a sound model for assessing the relationships between these constructs within a seminary sample. Additionally, seminarians were found to have higher rates of anxiety and depression when compared to the general population. Together, findings indicate that clinical care for seminarians may be best if implemented from a global systemic perspective.
RESUMEN
Krabbe disease is a rare autosomal recessive neurodegenerative disease, caused by mutations in the GALC gene, which encodes for the lysosomal enzyme galactocerebrosidase. Typical clinical manifestations of Krabbe include psychomotor deterioration, visual loss, seizures, and spasticity, that result from central nervous system demyelination. We report a case of a 35-year-old male with Krabbe who presented in adulthood with isolated severe, upper extremity predominant demyelinating sensorimotor polyneuropathy and did not develop other distinguishing clinical or radiological features of Krabbe until the later stages of the disease. The patient's diagnostic odyssey lasted 13 years from presentation to diagnosis, which was ultimately determined with the use of whole exome sequencing (WES) at the age of 48 years. The expanding phenotypic spectrum of adult-onset Krabbe Disease (AOKD) presents a diagnostic challenge that can lead to diagnostic delays and potentially affect treatment options. Our patient's case underscores the importance of pursuing WES in those with undiagnosed progressive neuromuscular disorders.
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Leucodistrofia de Células Globoides , Enfermedades Neurodegenerativas , Polineuropatías , Adulto , Masculino , Humanos , Persona de Mediana Edad , Leucodistrofia de Células Globoides/complicaciones , Leucodistrofia de Células Globoides/diagnóstico , Leucodistrofia de Células Globoides/genética , Galactosilceramidasa , MutaciónRESUMEN
With the increasing use of CT and MRI for diagnostic imaging and planning of interventional procedures, it is important for veterinary radiologists to be familiar with variations in normal vascular anatomy and not mistake them for pathology. The arterial blood supply to the cranial abdominal viscera is provided by the celiac and the cranial mesenteric arteries. A common celiacomesenteric trunk (CMT) has been reported as a rare anatomical variant in dogs. The goals of this retrospective, observational, cross-sectional prevalence study were to determine the prevalence of a CMT in dogs with non-abdominal disease and compare it to the prevalence in dogs with portosystemic shunts (PSS). Magnetic resonance imaging studies of the thoracolumbar and lumbosacral spine in dogs that included the origin of the celiac and cranial mesenteric arteries and dual-phase CT angiography studies of the abdomen in dogs with portosystemic shunts were retrospectively reviewed by a veterinary student and a board-certified veterinary radiologist. The prevalence of a CMT was determined as the proportion of dogs diagnosed with this vascular anomaly in the MRI and CT group, respectively. Fisher's exact test was used to determine any association of a CMT with the concurrent presence of a PSS, sex, and breed size. A CMT was identified in seven of 606 (1.2%) MRI studies and in none of 47 abdominal CT studies. There was no association between the presence of a CMT and PSS (P = 1.000), sex (P = .4694), or breed size (P = 1.000). A CMT is a rare incidental finding in dogs.
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Angiografía por Tomografía Computarizada , Derivación Portosistémica Quirúrgica , Abdomen , Animales , Angiografía por Tomografía Computarizada/veterinaria , Estudios Transversales , Perros , Humanos , Derivación Portosistémica Quirúrgica/veterinaria , Estudios RetrospectivosRESUMEN
Tropomodulins are a family of important regulators of actin dynamics at the pointed ends of actin filaments. Four isoforms of tropomodulin, Tmod1-Tmod4, are expressed in vertebrates. Binding of tropomodulin to the pointed end is dependent on tropomyosin, an actin binding protein that itself is represented in mammals by up to 40 isoforms. The understanding of the regulatory role of the tropomodulin/tropomyosin molecular diversity has been limited due to the lack of a three-dimensional structure of the tropomodulin/tropomyosin complex. In this study, we mapped tropomyosin residues interacting with two tropomyosin-binding sites of tropomodulin and generated a three-dimensional model of the tropomodulin/tropomyosin complex for each of these sites. The models were refined by molecular dynamics simulations and validated via building a self-consistent three-dimensional model of tropomodulin assembly at the pointed end. The model of the pointed-end Tmod assembly offers new insights in how Tmod binding ensures tight control over the pointed end dynamics.
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Citoesqueleto de Actina/química , Simulación de Dinámica Molecular , Tropomodulina/química , Animales , Ratones , Isoformas de Proteínas/químicaRESUMEN
Purpose: Inhibitor of differentiation (Id) proteins are helix-loop-helix (HLH) transcriptional repressors that modulate a range of developmental and cellular processes, including cell differentiation and cell cycle mobilization. The inhibitor of differentiation 3 (Id3) gene, a member of the Id gene family, governs the expression and progression of transforming growth factor beta (TGFß)-mediated cell differentiation. In the face of mechanical, chemical, or surgical corneal insults, corneal keratocytes differentiate into myofibroblasts for wound repair. Excessive development or persistence or both of myofibroblasts after wound repair results in corneal haze that compromises corneal clarity and visual function. The objective of this study was to investigate whether Id3 overexpression in human corneal stromal fibroblasts governs TGFß-driven cellular differentiation and inhibits keratocyte to myofibroblast transformation. Methods: Primary human corneal stromal fibroblast (h-CSF) cultures were generated from donor human corneas. Human corneal myofibroblasts (h-CMFs) were produced by growing h-CSF in the presence of TGFß1 under serum-free conditions. The Id3 gene was cloned into a mammalian expression vector (pcDNA3 mCherry LIC cloning vector), and the nucleotide sequence of the vector constructs was confirmed with sequencing as well as through restriction enzyme analysis. The Id3 mammalian overexpression vector was introduced into h-CSFs using a lipofectamine transfection kit. The expression of Id3 in selected clones was characterized with quantitative real-time PCR (qRT-PCR), immunocytochemistry, and western blotting. Phase contrast microscopy and trypan blue exclusion assays were used to evaluate the effects of the transfer of the Id3 gene on the hCSF phenotype and viability, respectively. To analyze the inhibitory effects of the Id3 gene transfer on TGFß-induced formation of h-CMFs, expression of the mRNA and protein of the myofibroblast marker alpha smooth muscle actin (α-SMA) was examined with qRT-PCR, western blotting, and immunocytochemistry. Student t test, analysis of variance (ANOVA), and Bonferroni adjustment for repeated measures were used for statistical analysis. Results: The results indicate that Id3 overexpression does not alter the cellular phenotype or viability of h-CSFs. Overexpression of the Id3 gene in h-CSF cells grown in the presence of TGFß1 under serum-free conditions showed a statistically significant decrease (76.3±4.3%) in α-SMA expression (p<0.01) compared to the naked-vector transfected or non-transfected h-CSF cells. Id3-transfected, naked-vector transfected, and non-transfected h-CSF cells grown in the absence of TGFß1 showed the expected low expression of α-SMA (0-5%). Furthermore, Id3 overexpression statistically significantly decreased TGFß-induced mRNA levels of profibrogenic genes such as fibronectin, collagen type I, and collagen type IV (1.80±0.26-, 1.70±0.35- and 1.70±0.36-fold, respectively; p<0.05) that a play role in stromal matrix modulation and corneal wound healing. Results of the protein analysis with western blotting indicated that Id3 overexpression in h-CSF cells effectively slows TGFß-driven differentiation and formation of h-CMFs. Results for subsequent overexpression studies showed that this process occurs through the regulation of E2A, a TATA box protein. Conclusions: Id3 regulates TGFß-driven differentiation of h-CSFs and formation of h-CMFs in vitro. Targeted Id3 gene delivery has potential to treat corneal fibrosis and reestablish corneal clarity in vivo.
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Diferenciación Celular/genética , Sustancia Propia/citología , Fibroblastos/citología , Proteínas Inhibidoras de la Diferenciación/genética , Proteínas de Neoplasias/genética , Biomarcadores/metabolismo , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Forma de la Célula/efectos de los fármacos , Forma de la Célula/genética , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibrosis , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Proteínas Inhibidoras de la Diferenciación/metabolismo , Modelos Biológicos , Miofibroblastos/citología , Miofibroblastos/efectos de los fármacos , Miofibroblastos/metabolismo , Proteínas de Neoplasias/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reproducibilidad de los Resultados , Factor de Crecimiento Transformador beta1/farmacologíaRESUMEN
Critical weight loss, as defined by ≥5% decrease in body weight, has been associated with increased morbidity and mortality in human patients with cancers of the head and neck. Weight loss has anecdotally been reported to occur frequently in veterinary patients undergoing radiation therapy and is hypothesized to be more severe in patients with cancers of the head and neck, along with those hospitalized during radiation therapy. The primary objective of this retrospective study was to evaluate the occurrence of critical weight loss in canine cancer bearing patients undergoing either definitive or palliative radiation protocols and to determine if weight changes were associated with radiation toxicity, tumour location or patient hospitalization status. Data from 47 dogs who underwent definitive and 43 dogs who underwent palliative radiation protocols at the University of Tennessee were included for analysis. Dogs were categorized based on tumour location (head/neck or other), hospitalization status (boarded or non-boarded) and radiation toxicity score. Weight recorded at the start of treatment, midway through treatment and at the final treatment was used for analysis. No significant differences were found in regard to weight change over time, location or hospitalization status when evaluated for both protocols. Overall, 5/90 dogs (5.5%) lost 5% or more of their body weight during therapy, and 7/90 dogs (7.7%) gained 5% or more of their body weight. The results of the current study suggest that critical weight loss occurs in a small percentage of canine patients undergoing radiation therapy, contrary to what is often anecdotally reported.
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Enfermedades de los Perros/radioterapia , Neoplasias/veterinaria , Radioterapia/veterinaria , Pérdida de Peso , Animales , Perros , Femenino , Masculino , Neoplasias/radioterapia , Radioterapia/efectos adversos , Estudios Retrospectivos , Factores de RiesgoRESUMEN
OBJECTIVE: Passive administration of broadly neutralizing antibodies has been shown to protect against both vaginal and rectal challenge in the simian/human immunodeficiency virus (SHIV)/macaque model of HIV transmission. However, the relative efficacy of antibody against the two modes of exposure is unknown and, given differences in the composition and immunology of the two tissue compartments, this is an important gap in knowledge. To investigate the significance of the challenge route for antibody-mediated protection, we performed a comparative protection study in macaques using the highly potent human monoclonal antibody, PGT126. DESIGN: Animals were administered PGT126 at three different doses before challenged either vaginally or rectally with a single dose of SHIVSF163P3. METHODS: Viral loads, PGT126 serum concentrations, and serum neutralizing titers were monitored. RESULTS: In vaginally challenged animals, sterilizing immunity was achieved in all animals administered 10âmg/kg, in two of five animals administered 2âmg/kg and in one of five animals administered 0.4âmg/kg PGT126. Comparable protection was observed for the corresponding groups challenged rectally as sterilizing immunity was achieved in three of four animals administered 10âmg/kg, in two of four animals administered 2âmg/kg and in none of four animals administered 0.4âmg/kg PGT126. Serological analysis showed similar serum concentrations of PGT126 and serum neutralization titers in animals administered the same antibody dose. CONCLUSION: Our data suggest that broadly neutralizing antibody-mediated protection is not strongly dependent on the mucosal route of challenge, which indicates that a vaccine aimed to induce a neutralizing antibody response would have broadly similar efficacy against both primary transmission routes for HIV.
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Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos Anti-VIH/administración & dosificación , Infecciones por VIH/prevención & control , VIH/inmunología , Recto/inmunología , Vagina/inmunología , Animales , Modelos Animales de Enfermedad , Femenino , Macaca , Resultado del Tratamiento , Carga ViralRESUMEN
The earliest events following mucosal HIV-1 infection, prior to measurable viremia, remain poorly understood. Here, by detailed necropsy studies, we show that the virus can rapidly disseminate following mucosal SIV infection of rhesus monkeys and trigger components of the inflammasome, both at the site of inoculation and at early sites of distal virus spread. By 24 hr following inoculation, a proinflammatory signature that lacked antiviral restriction factors was observed in viral RNA-positive tissues. The early innate response included expression of NLRX1, which inhibits antiviral responses, and activation of the TGF-ß pathway, which negatively regulates adaptive immune responses. These data suggest a model in which the virus triggers specific host mechanisms that suppress the generation of antiviral innate and adaptive immune responses in the first few days of infection, thus facilitating its own replication. These findings have important implications for the development of vaccines and other strategies to prevent infection.
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Inflamasomas/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/fisiología , Animales , Médula Ósea/inmunología , Inmunidad Innata , Inmunidad Mucosa , Células Asesinas Naturales/inmunología , Macaca mulatta , Proteínas Mitocondriales/metabolismo , Monocitos/inmunología , Linfocitos T/inmunología , Transcriptoma , Factor de Crecimiento Transformador beta/metabolismo , Replicación ViralRESUMEN
Preclinical studies of viral vector-based HIV-1 vaccine candidates have previously shown partial protection against neutralization-resistant virus challenges in rhesus monkeys. In this study, we evaluated the protective efficacy of adenovirus serotype 26 (Ad26) vector priming followed by purified envelope (Env) glycoprotein boosting. Rhesus monkeys primed with Ad26 vectors expressing SIVsmE543 Env, Gag, and Pol and boosted with AS01B-adjuvanted SIVmac32H Env gp140 demonstrated complete protection in 50% of vaccinated animals against a series of repeated, heterologous, intrarectal SIVmac251 challenges that infected all controls. Protective efficacy correlated with the functionality of Env-specific antibody responses. Comparable protection was also observed with a similar Ad/Env vaccine against repeated, heterologous, intrarectal SHIV-SF162P3 challenges. These data demonstrate robust protection by Ad/Env vaccines against acquisition of neutralization-resistant virus challenges in rhesus monkeys.
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Vacunas contra el SIDA/inmunología , Vacunas contra el Adenovirus/inmunología , Productos del Gen env/inmunología , VIH-1/inmunología , Vacunas contra el SIDAS/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Traslado Adoptivo , Animales , Anticuerpos Neutralizantes/inmunología , Femenino , Productos del Gen gag/inmunología , Productos del Gen pol/inmunología , Vectores Genéticos/inmunología , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Inmunización Secundaria , Macaca mulatta , Masculino , Virus de la Inmunodeficiencia de los Simios/inmunologíaRESUMEN
The viral reservoir represents a critical challenge for human immunodeficiency virus type 1 (HIV-1) eradication strategies. However, it remains unclear when and where the viral reservoir is seeded during acute infection and the extent to which it is susceptible to early antiretroviral therapy (ART). Here we show that the viral reservoir is seeded rapidly after mucosal simian immunodeficiency virus (SIV) infection of rhesus monkeys and before systemic viraemia. We initiated suppressive ART in groups of monkeys on days 3, 7, 10 and 14 after intrarectal SIVMAC251 infection. Treatment with ART on day 3 blocked the emergence of viral RNA and proviral DNA in peripheral blood and also substantially reduced levels of proviral DNA in lymph nodes and gastrointestinal mucosa as compared with treatment at later time points. In addition, treatment on day 3 abrogated the induction of SIV-specific humoral and cellular immune responses. Nevertheless, after discontinuation of ART following 24 weeks of fully suppressive therapy, virus rebounded in all animals, although the monkeys that were treated on day 3 exhibited a delayed viral rebound as compared with those treated on days 7, 10 and 14. The time to viral rebound correlated with total viraemia during acute infection and with proviral DNA at the time of ART discontinuation. These data demonstrate that the viral reservoir is seeded rapidly after intrarectal SIV infection of rhesus monkeys, during the 'eclipse' phase, and before detectable viraemia. This strikingly early seeding of the refractory viral reservoir raises important new challenges for HIV-1 eradication strategies.
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Macaca mulatta/virología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/crecimiento & desarrollo , Carga Viral , Viremia/virología , Animales , Antirretrovirales/administración & dosificación , Antirretrovirales/farmacología , Antirretrovirales/uso terapéutico , Portador Sano/tratamiento farmacológico , Portador Sano/virología , ADN Viral/análisis , ADN Viral/biosíntesis , ADN Viral/sangre , Modelos Animales de Enfermedad , Femenino , Cinética , Macaca mulatta/inmunología , Masculino , Provirus/genética , ARN Viral/sangre , Recto/virología , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacos , Virus de la Inmunodeficiencia de los Simios/inmunología , Virus de la Inmunodeficiencia de los Simios/fisiología , Factores de Tiempo , Insuficiencia del Tratamiento , Carga Viral/efectos de los fármacos , Viremia/tratamiento farmacológico , Replicación Viral/efectos de los fármacosRESUMEN
UNLABELLED: Foreskin is the principal site of heterosexual HIV-1 infection in men. However, little is known about HIV-1-specific immune responses or inflammation in foreskin. To the best of our knowledge, no previous studies have assessed immune responses to candidate HIV-1 vaccines in foreskin. Using the rhesus monkey model, we show that intramuscular immunization with adenovirus serotype 26 and 35 vectors expressing SIV antigens elicited durable SIV Gag-specific CD4(+) and CD8(+) T cell responses in foreskin that were detectable for more than 1 year following vaccination. Gag-specific CD4(+) and CD8(+) T cells were also detectable in foreskin of SIV- and SHIV-infected animals and were at least comparable in magnitude to those in peripheral blood. However, unlike peripheral blood T cells, the majority of foreskin T cells exhibited transitional memory or effector memory phenotype and expressed higher levels of the activation markers CD69, HLA-DR, and CCR5, although vaccination did not further enhance foreskin CD4(+) T cell activation. These findings suggest that systemic vaccination strategies can elicit potentially important SIV-specific cellular immunity in foreskin. Further characterization of vaccine-elicited immune responses and inflammation in foreskin is warranted. IMPORTANCE: We demonstrate here the induction of SIV-specific cellular immune responses in foreskin by adenovirus serotype 26 and 35 vaccine vectors. Foreskin T cells were more activated than peripheral blood T cells, but foreskin T cells were not further activated by vaccination. These findings suggest that alternative serotype adenovirus vectors induce potentially important immune responses in foreskin.
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Adenoviridae/genética , Portadores de Fármacos , Prepucio/inmunología , Vectores Genéticos , Vacunas contra el SIDAS/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Linfocitos T/inmunología , Animales , Inmunofenotipificación , Inyecciones Intramusculares , Macaca mulatta , Masculino , Vacunas contra el SIDAS/administración & dosificación , Vacunas contra el SIDAS/genética , Virus de la Inmunodeficiencia de los Simios/genética , Factores de TiempoAsunto(s)
Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/farmacocinética , Microinyecciones/instrumentación , Agujas , Absorción Cutánea/fisiología , Vacunas Virales/administración & dosificación , Vacunas Virales/farmacocinética , Administración Cutánea , Animales , Diseño de Equipo , Análisis de Falla de Equipo , Humanos , MacacaRESUMEN
The global diversity of HIV-1 represents a critical challenge facing HIV-1 vaccine development. HIV-1 mosaic antigens are bioinformatically optimized immunogens designed for improved coverage of HIV-1 diversity. However, the protective efficacy of such global HIV-1 vaccine antigens has not previously been evaluated. Here, we demonstrate the capacity of bivalent HIV-1 mosaic antigens to protect rhesus monkeys against acquisition of infection following heterologous challenges with the difficult-to-neutralize simian-human immunodeficiency virus SHIV-SF162P3. Adenovirus/poxvirus and adenovirus/adenovirus vector-based vaccines expressing HIV-1 mosaic Env, Gag, and Pol afforded a significant reduction in the per-exposure acquisition risk following repetitive, intrarectal SHIV-SF162P3 challenges. Protection against acquisition of infection correlated with vaccine-elicited binding, neutralizing, and functional nonneutralizing antibodies, suggesting that the coordinated activity of multiple antibody functions may contribute to protection against difficult-to-neutralize viruses. These data demonstrate the protective efficacy of HIV-1 mosaic antigens and suggest a potential strategy for the development of a global HIV-1 vaccine. PAPERCLIP:
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Vacunas contra el SIDA/inmunología , VIH-1 , Animales , Formación de Anticuerpos , Femenino , Antígenos VIH/inmunología , Proteínas del Virus de la Inmunodeficiencia Humana/inmunología , Inmunidad Celular , Macaca mulatta , Masculino , Datos de Secuencia Molecular , Organismos Libres de Patógenos EspecíficosRESUMEN
Human immunodeficiency virus type 1 (HIV-1)-specific monoclonal antibodies with extraordinary potency and breadth have recently been described. In humanized mice, combinations of monoclonal antibodies have been shown to suppress viraemia, but the therapeutic potential of these monoclonal antibodies has not yet been evaluated in primates with an intact immune system. Here we show that administration of a cocktail of HIV-1-specific monoclonal antibodies, as well as the single glycan-dependent monoclonal antibody PGT121, resulted in a rapid and precipitous decline of plasma viraemia to undetectable levels in rhesus monkeys chronically infected with the pathogenic simian-human immunodeficiency virus SHIV-SF162P3. A single monoclonal antibody infusion afforded up to a 3.1 log decline of plasma viral RNA in 7 days and also reduced proviral DNA in peripheral blood, gastrointestinal mucosa and lymph nodes without the development of viral resistance. Moreover, after monoclonal antibody administration, host Gag-specific T-lymphocyte responses showed improved functionality. Virus rebounded in most animals after a median of 56 days when serum monoclonal antibody titres had declined to undetectable levels, although, notably, a subset of animals maintained long-term virological control in the absence of further monoclonal antibody infusions. These data demonstrate a profound therapeutic effect of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys as well as an impact on host immune responses. Our findings strongly encourage the investigation of monoclonal antibody therapy for HIV-1 in humans.
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Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Neutralizantes/uso terapéutico , VIH-1/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/terapia , Virus de la Inmunodeficiencia de los Simios/fisiología , Animales , ADN Viral/sangre , Anticuerpos Anti-VIH/inmunología , Macaca mulatta , Linfocitos T/inmunología , Viremia/terapiaRESUMEN
A global HIV-1 vaccine will likely need to induce immune responses against conserved HIV-1 regions to contend with the profound genetic diversity of HIV-1. Here we evaluated the capacity of immunogens consisting of only highly conserved HIV-1 sequences that are aimed at focusing cellular immune responses on these potentially critical regions. We assessed in rhesus monkeys the breadth and magnitude of T lymphocyte responses elicited by adenovirus vectors expressing either full-length HIV-1 Gag/Pol/Env immunogens or concatenated immunogens consisting of only highly conserved HIV-1 sequences. Surprisingly, we found that the full-length immunogens induced comparable breadth (P = 1.0) and greater magnitude (P = 0.01) of CD8(+) T lymphocyte responses against conserved HIV-1 regions compared with the conserved-region-only immunogens. Moreover, the full-length immunogens induced a 5-fold increased total breadth of HIV-1-specific T lymphocyte responses compared with the conserved-region-only immunogens (P = 0.007). These results suggest that full-length HIV-1 immunogens elicit a substantially increased magnitude and breadth of cellular immune responses compared with conserved-region-only HIV-1 immunogens, including greater magnitude and comparable breadth of responses against conserved sequences.
Asunto(s)
Vacunas contra el SIDA/administración & dosificación , Vacunas contra el SIDA/inmunología , Antígenos Virales/inmunología , Linfocitos T CD8-positivos/inmunología , VIH-1/inmunología , Vacunas contra el SIDA/genética , Adenoviridae/genética , Animales , Portadores de Fármacos , Vectores Genéticos , Macaca mulatta , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/genética , Vacunas Sintéticas/inmunología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/inmunología , Productos del Gen pol del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen pol del Virus de la Inmunodeficiencia Humana/inmunologíaRESUMEN
BACKGROUND: Recommendations about precautionary behaviors are a key part of public health responses to infectious disease threats such as the 2009 H1N1 pandemic. Individuals' interpretation of recommendations, willingness to comply, and factors predicting willingness were examined. METHODS: A telephone survey of adult residents of New York State was conducted (N = 807). Respondents reported how they interpreted recommendations, willingness to engage in recommended actions, risk perceptions for H1N1 infection, and perceived efficacy of recommendations. Demographic characteristics were used to calculate sampling weights to obtain population-representative estimates. RESULTS: There was substantial variability in interpretation of preventive actions. Willingness to engage in preventive actions also varied substantially; vaccination willingness was substantially lower than other preventive actions. No pattern of demographic characteristics consistently predicted willingness. Perceived efficacy was associated with willingness for all recommendations, and perceived severity was associated with willingness for some recommendations. CONCLUSIONS: Results suggest that individual interpretation of actions differ widely. The results suggest that current recommendations are not clear to laypeople and are open to different interpretations. These varying interpretations should be considered in crafting public health messages about precautionary behaviors.