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1.
BMJ ; 368: m517, 2020 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-32205307

RESUMEN

The studyPowell J, Atherton H, Williams V, et al. Using online patient feedback to improve NHS services: the INQUIRE multimethod study. Health Serv Deliv Res 2019;7:38.This project was funded by the NIHR Health Services and Delivery Research programme (project number HS&DR 14/04/48).To read the full NIHR Signal, go to: https://discover.dc.nihr.ac.uk/content/signal-000861/online-patient-feedback-is-mostly-positive-but-is-not-being-used-effectively.


Asunto(s)
Retroalimentación , Satisfacción del Paciente , Medicina Estatal , Participación de la Comunidad , Humanos , Medicina Estatal/normas , Reino Unido
2.
BMJ ; 368: l6768, 2020 01 10.
Artículo en Inglés | MEDLINE | ID: mdl-31924664

RESUMEN

The studyCabral C, Horwood J, Symonds J, et al. Understanding the influence of parent-clinician communication on antibiotic prescribing for children with respiratory tract infections in primary care: a qualitative observational study using a conversation analysis approach. BMC Fam Pract 2019;20:102.This project was funded by the NIHR School for Primary Care Research Programme (project number SPCR204).To read the full NIHR Signal, go to: https://discover.dc.nihr.ac.uk/content/signal-000829/gps-assessment-not-parental-expectation-drives-antibiotic-prescribing.


Asunto(s)
Antibacterianos , Infecciones del Sistema Respiratorio , Niño , Humanos , Motivación , Padres , Atención Primaria de Salud
3.
Artículo en Inglés | MEDLINE | ID: mdl-31600386

RESUMEN

Importance: Despite various barriers identified to early pediatric access to cochlear implantation, barriers to timely access to pediatric hearing aids are not well characterized. Objective: To identify socioeconomic, demographic, and clinical factors that may be associated with pediatric access to hearing aids. Design, Setting, and Participants: This retrospective cohort study included 90 patients aged 1 to 15 years who were referred for auditory brainstem response (ABR) testing and evaluation for hearing aids at a single tertiary care academic medical center from March 2004 to July 2018. Children who did not receive both ABR testing and hearing aids at the same center were excluded from analysis. Main Outcomes and Measures: Associations of insurance type (private vs public), race/ethnicity (white vs other), primary language (English vs other), cause of hearing loss (complex vs not complex), zip code, hearing aid manufacturer, and severity of hearing loss (in decibels) with the duration of intervals from newborn hearing screening to ABR testing, from ABR testing to ordering of hearing aids, and from ABR testing to dispensing of hearing aids. Results: Of the 90 patients, mean (SD) age was 5.6 (3.7) years, 56% were female, and 77 (86%) were non-Hispanic. Results of χ2 tests indicated significant assocations existed between public insurance and race/ethnicity and between public insurance and primary language other than English. Variables associated with the interval from newborn hearing screening to ABR testing included insurance type (mean difference, 7.4 months; 95% CI, 2.6-12.2 months) and race/ethnicity (mean difference, 6.9 months; 95% CI, 2.7-11.1 months). Increased delays between birth and a child's first ABR test were associated with public insurance (mean difference, 6.0 months; 95% CI, 1.8-10.2 months) and race/ethnicity other than white (mean difference, 6.0 months; 95% CI, 2.3-9.7 months). The mean time from birth to initial ABR testing was a mean of 6 months longer for patients from non-English-speaking families than for those from English-speaking families (mean [SD] interval, 14.9 [16.3] months vs 9.0 [8.5] months), although the difference was not statistically significant. Severity of hearing loss was associated with a decrease in the interval from ABR testing to ordering of hearing aids after accounting for other potential barriers (odds ratio, 0.6; 95% CI, 0.4-0.9). Zip code and complexity of the child's medical condition did not appear to be associated with timely access to pediatric hearing aids. Conclusions and Relevance: This study's findings suggest that insurance type, race/ethnicity, and primary language may be barriers associated with pediatric access to hearing aids, with the greatest difference observed in time to initial ABR testing. Clinical severity of hearing loss appeared to be associated with a significant decrease in time from ABR testing to ordering of hearing aids. Greater efforts to assist parents with ABR testing and coordination of follow-up may help improve access for other at-risk children.

4.
Sci Rep ; 9(1): 11263, 2019 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-31375773

RESUMEN

Evolution of cellular innate immune genes in response to viral threats represents a rich area of study for understanding complex events that shape mammalian genomes. One of these genes, TRIM5, is a retroviral restriction factor that mediates a post-entry block to infection. Previous studies on the genomic cluster that contains TRIM5 identified different patterns of gene amplification and the independent birth of CypA gene fusions in various primate species. However, the evolution of Trim5 in the largest order of mammals, Rodentia, remains poorly characterized. Here, we present an expansive phylogenetic and genomic analysis of the Trim5 cluster in rodents. Our findings reveal substantial evolutionary changes including gene amplifications, rearrangements, loss and fusion. We describe the first independent evolution of TrimCyp fusion genes in rodents. We show that the TrimCyp gene found in some Peromyscus species was acquired about 2 million years ago. When ectopically expressed, the P. maniculatus TRIMCyp shows anti-retroviral activity that is reversed by cyclosporine, but it does not activate Nf-κB or AP-1 promoters, unlike the primate TRIMCyps. These results describe a complex pattern of differential gene amplification in the Trim5 cluster of rodents and identify the first functional TrimCyp fusion gene outside of primates and tree shrews.

5.
BMJ Open ; 9(3): e024324, 2019 03 23.
Artículo en Inglés | MEDLINE | ID: mdl-30904850

RESUMEN

OBJECTIVES: To estimate the potential impact of the addition of culture-based screening for group B streptococcus (GBS) carriage in pregnancy to a risk-based prevention policy in the UK. We aimed to establish agreement within a multidisciplinary group of key stakeholders on the model input parameters. DESIGN: Deterministic model using a consensus approach for the selection of input parameters. SETTING AND PARTICIPANTS: A theoretical annual cohort of 711 999 live births in the UK (excluding births by elective caesarean section). INTERVENTIONS: Culture-based screening for GBS at 35-37 weeks of pregnancy added to the recommended risk-based prevention policy in place on the date of modelling. OUTCOME MEASURES: Outcomes assessed included use of intrapartum antibiotic prophylaxis (IAP), early onset GBS (EOGBS), EOGBS mortality, severe EOGBS-related morbidity and maternal penicillin anaphylaxis. RESULTS: With no prophylaxis strategy, the model estimated that there would be 421 cases of culture positive EOGBS in a year (0.59/1000 live births). In the risk-based prophylaxis scenario, 30 666 women were estimated to receive IAP and 70 cases of EOGBS were prevented. Addition of screening resulted in a further 96 260 women receiving IAP and the prevention of an additional 52 to 57 cases of EOGBS. This resulted in the prevention of three EOGBS deaths and four cases of severe disability. With screening, an additional 1675 to 1854 women receive IAP to prevent one EOGBS case and 24 065 to 32 087 receive IAP to prevent one EOGBS death. CONCLUSIONS: The evidence base available for a broad range of model input parameters was limited, leading to uncertainty in the estimates produced by the model. Where data was limited, the model input parameters were agreed with the multidisciplinary stakeholder group, the first time this has been done to our knowledge. The main impact of screening is likely to be on the large group of low-risk women where the clinical impact of EOGBS tends to be less severe. This model suggests that the reduction in mortality and severe disability due to EOGBS with antenatal GBS screening is likely to be very limited, with a high rate of overdetection and overuse of antibiotics.

6.
BMJ ; 367: l5991, 2019 12 30.
Artículo en Inglés | MEDLINE | ID: mdl-31888868

RESUMEN

The studyButler CC, Gillespie D, White P, et al. C-reactive protein testing to guide antibiotic prescribing for COPD exacerbations. N Engl J Med 2019;381:111-20.This research was funded by the NIHR Technology Assessment Programme (project number 12/33/12). The testing machines used in the study were loaned to researchers by the manufacturer, who also provided training on their use. The manufacturer had no other role in any part of the trial.To read the full NIHR Signal, go to https://discover.dc.nihr.ac.uk/content/signal-000820/crp-testing-safely-reduces-antibiotic-use-for-copd-flare-ups.


Asunto(s)
Medicina General , Enfermedad Pulmonar Obstructiva Crónica , Antibacterianos , Proteína C-Reactiva , Medicina Familiar y Comunitaria , Humanos
7.
BMJ ; 367: l5994, 2019 12 30.
Artículo en Inglés | MEDLINE | ID: mdl-31888877

RESUMEN

The studyBeard D, Davies L, Cook J, et al. The clinical and cost-effectiveness of total versus partial knee replacement in patients with medial compartment osteoarthritis (TOPKAT): 5-year outcomes of a randomised controlled trial. Lancet 2019;394:746-56.The study was funded by the NIHR Health Technology Assessment Programme (project number 08/14/08).To read the full NIHR Signal, go to https://discover.dc.nihr.ac.uk/content/signal-000824/partial-knee-replacement-could-be-first-choice-in-some-patients.


Asunto(s)
Artroplastia de Reemplazo de Rodilla , Osteoartritis , Análisis Costo-Beneficio , Humanos , Evaluación de la Tecnología Biomédica
8.
Physiol Rep ; 6(17): e13840, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-30175552

RESUMEN

Fetal insulin is critical for regulation of growth. Insulin concentrations are partly determined by the amount of ß-cells present and their insulin content. Insulin-like growth factor-1 (IGF-1) is a fetal anabolic growth factor which also impacts ß-cell mass in models of ß-cell injury and diabetes. The extent to which circulating concentrations of IGF-1 impact fetal ß-cell mass and pancreatic insulin content is unknown. We hypothesized that an infusion of an IGF-1 analog for 1 week into the late gestation fetal sheep circulation would increase ß-cell mass, pancreatic islet size, and pancreatic insulin content. After the 1-week infusion, pancreatic insulin concentrations were 80% higher than control fetuses (P < 0.05), but there were no differences in ß-cell area, ß-cell mass, or pancreatic vascularity. However, pancreatic islet vascularity was 15% higher in IGF-1 fetuses and pancreatic VEGFA, HGF, IGF1, and IGF2 mRNA expressions were 70-90% higher in IGF-1 fetuses compared to control fetuses (P < 0.05). Plasma oxygen, glucose, and insulin concentrations were 25%, 22%, and 84% lower in IGF-1 fetuses, respectively (P < 0.05). The previously described role for IGF-1 as a ß-cell growth factor may be more relevant for local paracrine signaling in the pancreas compared to circulating endocrine signaling.


Asunto(s)
Sangre Fetal/metabolismo , Factor I del Crecimiento Similar a la Insulina/farmacología , Insulina/sangre , Islotes Pancreáticos/metabolismo , Animales , Arterias/metabolismo , Glucemia/análisis , Femenino , Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/administración & dosificación , Factor II del Crecimiento Similar a la Insulina/metabolismo , Islotes Pancreáticos/irrigación sanguínea , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/embriología , Masculino , Oxígeno/sangre , Ovinos
9.
Viruses ; 10(8)2018 08 09.
Artículo en Inglés | MEDLINE | ID: mdl-30096897

RESUMEN

Naturally-occurring lymphomagenesis is induced by mouse leukemia viruses (MLVs) carried as endogenous retroviruses (ERVs). Replicating the ecotropic MLVs recombines with polytropic (P-ERVs) and xenotropic ERVs (X-ERVs) to generate pathogenic viruses with an altered host range. While most recovered nonecotropic recombinants have a polytropic host range, the X-MLVs are also present in the pre-leukemic tissues. We analyzed two such isolates from the AKR mice to identify their ERV progenitors and to look for evidence of recombination. AKR40 resembles the active X-ERV Bxv1, while AKR6 has a Bxv1-like backbone with substitutions that alter the long terminal repeat (LTR) enhancer and the envelope (env). AKR6 has a modified xenotropic host range, and its Env residue changes all lie outside of the domain that governs the receptor choice. The AKR6 segment spanning the two substitutions, but not the entire AKR6 env-LTR, exists as an ERV, termed Xmv67, in AKR, but not in the C57BL/6 mice. This suggests that AKR6 is the product of one, not two, recombination events. Xmv67 originated in the Asian mice. These data indicate that the recombinant X-MLVs that can be generated during lymphomagenesis, describe a novel X-ERV subtype found in the AKR genome, but not in the C57BL/6 reference genome, and identify residues in the envelope C-terminus that may influence the host range.


Asunto(s)
Retrovirus Endógenos/genética , Evolución Molecular , Gammaretrovirus/genética , Virus de la Leucemia Murina/genética , Linfoma/virología , Recombinación Genética , Animales , Gammaretrovirus/aislamiento & purificación , Genoma Viral , Especificidad del Huésped , Virus de la Leucemia Murina/aislamiento & purificación , Ratones , Ratones Endogámicos AKR , Ratones Endogámicos C57BL , Receptores Virales/genética , Secuencias Repetidas Terminales
10.
J Virol ; 92(18)2018 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-29976659

RESUMEN

The laboratory mouse Fv1 gene encodes a retroviral restriction factor that mediates resistance to murine leukemia viruses (MLVs). Sequence similarity between Fv1 and the gag protein of the murine endogenous retrovirus L (MuERV-L) family of ERVs suggests that Fv1 was coopted from an ancient provirus. Previous evolutionary studies found Fv1 orthologs only in the genus Mus Here, we describe identification of orthologous Fv1 sequences in several species belonging to multiple families of rodents outside the genus Mus We show that these Fv1 orthologs are in the same region of conserved synteny, between the genes Miip and Mfn2, suggesting a minimum insertion time of 45 million years for the ancient progenitor of Fv1 Our analysis also revealed that Fv1 was not detectable or heavily mutated in some lineages in the superfamily Muroidea, while, in concert with previous findings in the genus Mus, we found strong evidence of positive selection of Fv1 in the African clade in the subfamily Muridae Residues identified as evolving under positive selection include those that have been previously found to be important for restriction of multiple retroviral lineages. Taken together, these findings suggest that the evolutionary origin of Fv1 substantially predates Mus evolution, that the rodent Fv1 has been shaped by lineage-specific differential selection pressures, and that Fv1 has long been evolving under positive selection in the rodent family Muridae, supporting a defensive role that significantly antedates exposure to MLVs.IMPORTANCE Retroviruses have adapted to living in concert with their hosts throughout vertebrate evolution. Over the years, the study of these relationships revealed the presence of host proteins called restriction factors that inhibit retroviral replication in host cells. The first of these restriction factors to be identified, encoded by the Fv1 gene found in mice, was thought to have originated in the genus Mus In this study, we utilized genome database searches and DNA sequencing to identify Fv1 copies in multiple rodent lineages. Our findings suggest a minimum time of insertion into the genome of rodents of 45 million years for the ancestral progenitor of Fv1 While Fv1 is not detectable in some lineages, we also identified full-length orthologs showing signatures of a molecular "arms race" in a family of rodent species indigenous to Africa. This finding suggests that Fv1 in these species has been coevolving with unidentified retroviruses for millions of years.


Asunto(s)
Proteínas/genética , Roedores/genética , Animales , Evolución Molecular , Ratones , Selección Genética
11.
Nat Med ; 24(9): 1482, 2018 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-29934536

RESUMEN

In the version of this article originally published, a URL provided in the Methods section was incorrect. The URL had a solidus at the end but should have appeared as http://www.nature.com/authors/policies/image.html. The error has been corrected in the PDF and HTML versions of this article.

12.
Nat Med ; 24(5): 610-616, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29662199

RESUMEN

In the absence of an effective and safe vaccine against HIV-1, the administration of broadly neutralizing antibodies (bNAbs) represents a logical alternative approach to prevent virus transmission. Here, we introduced two mutations encoding amino acid substitutions (M428L and N434S, collectively referred to as 'LS') into the genes encoding the crystallizable fragment domains of the highly potent HIV-specific 3BNC117 and 10-1074 bNAbs to increase their half-lives and evaluated their efficacy in blocking infection following repeated low-dose mucosal challenges of rhesus macaques (Macaca mulatta) with the tier 2 SHIVAD8-EO. A single intravenous infusion of 10-1074-LS monoclonal antibodies markedly delayed virus acquisition for 18 to 37 weeks (median, 27 weeks), whereas the protective effect of the 3BNC117-LS bNAb was more modest (provided protection for 11-23 weeks; median, 17 weeks). Serum concentrations of the 10-1074-LS monoclonal antibody gradually declined and became undetectable in all recipients between weeks 26 and 41, whereas the 3BNC117-LS bNAb exhibited a shorter half-life. To model immunoprophylaxis against genetically diverse and/or neutralization-resistant HIV-1 strains, a combination of the 3BNC117-LS plus 10-1074-LS monoclonal antibodies was injected into macaques via the more clinically relevant subcutaneous route. Even though the administered mixture contained an amount of each bNAb that was nearly threefold less than the quantity of the single monoclonal antibody in the intravenous injections, the monoclonal antibody combination still protected macaques for a median of 20 weeks. The extended period of protection observed in macaques for the 3BNC117-LS plus 10-1074-LS combination could translate into an effective semiannual or annual immunoprophylaxis regimen for preventing HIV-1 infections in humans.


Asunto(s)
Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Virus de la Inmunodeficiencia de los Simios/inmunología , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/sangre , Formación de Anticuerpos/inmunología , Cristalización , Relación Dosis-Respuesta Inmunológica , Células HEK293 , Humanos , Inyecciones , Macaca mulatta , Membrana Mucosa/inmunología , Membrana Mucosa/virología , Mutación/genética , Pruebas de Neutralización , Probabilidad , Dominios Proteicos , Síndrome de Inmunodeficiencia Adquirida del Simio/sangre , Resultado del Tratamiento
13.
Nat Med ; 24(5): 658-666, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29662202

RESUMEN

Major depressive disorder (MDD) is considered a 'circuitopathy', and brain stimulation therapies hold promise for ameliorating MDD symptoms, including hippocampal dysfunction. It is unknown whether stimulation of upstream hippocampal circuitry, such as the entorhinal cortex (Ent), is antidepressive, although Ent stimulation improves learning and memory in mice and humans. Here we show that molecular targeting (Ent-specific knockdown of a psychosocial stress-induced protein) and chemogenetic stimulation of Ent neurons induce antidepressive-like effects in mice. Mechanistically, we show that Ent-stimulation-induced antidepressive-like behavior relies on the generation of new hippocampal neurons. Thus, controlled stimulation of Ent hippocampal afferents is antidepressive via increased hippocampal neurogenesis. These findings emphasize the power and potential of Ent glutamatergic afferent stimulation-previously well-known for its ability to influence learning and memory-for MDD treatment.


Asunto(s)
Antidepresivos/uso terapéutico , Giro Dentado/patología , Corteza Entorrinal/patología , Animales , Conducta Animal , Enfermedad Crónica , Dendritas/patología , Glutamatos/metabolismo , Células HEK293 , Humanos , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Red Nerviosa/metabolismo , Red Nerviosa/patología , Neurogénesis , Peroxinas/deficiencia , Peroxinas/metabolismo , Estrés Psicológico/complicaciones
14.
Adv Wound Care (New Rochelle) ; 6(8): 253-260, 2017 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-28831328

RESUMEN

Amputation rates during recent military conflicts were at an all-time high, but medical treatment of those amputations and attitudes of service members to get back to duty are also surging ahead. We present the cases of an active duty rescue C130 pilot with an above-the-knee amputation and a retired army sergeant with a below-the-knee amputation. Successful rehabilitation was augmented in both cases by using negative pressure incorporated in a custom prosthetic socket to accelerate incision closure, improve self-efficacy in wound care, and self-management, ultimately leading to faster recovery times, full engagement of the rehabilitation process, and return to active duty.

15.
J Virol ; 91(21)2017 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-28794032

RESUMEN

Ecotropic, xenotropic, and polytropic mouse leukemia viruses (E-, X-, and P-MLVs) exist in mice as infectious viruses and endogenous retroviruses (ERVs) inserted into mouse chromosomes. All three MLV subgroups are linked to leukemogenesis, which involves generation of recombinants with polytropic host range. Although P-MLVs are deemed to be the proximal agents of disease induction, few biologically characterized infectious P-MLVs have been sequenced for comparative analysis. We analyzed the complete genomes of 16 naturally occurring infectious P-MLVs, 12 of which were typed for pathogenic potential. We sought to identify ERV progenitors, recombinational hot spots, and segments that are always replaced, never replaced, or linked to pathogenesis or host range. Each P-MLV has an E-MLV backbone with P- or X-ERV replacements that together cover 100% of the recombinant genomes, with different substitution patterns for X- and P-ERVs. Two segments are always replaced, both coding for envelope (Env) protein segments: the N terminus of the surface subunit and the cytoplasmic tail R peptide. Viral gag gene replacements are influenced by host restriction genes Fv1 and Apobec3 Pathogenic potential maps to the env transmembrane subunit segment encoding the N-heptad repeat (HR1). Molecular dynamics simulations identified three novel interdomain salt bridges in the lymphomagenic virus HR1 that could affect structural stability, entry or sensitivity to host immune responses. The long terminal repeats of lymphomagenic P-MLVs are differentially altered by recombinations, duplications, or mutations. This analysis of the naturally occurring, sometimes pathogenic P-MLV recombinants defines the limits and extent of intersubgroup recombination and identifies specific sequence changes linked to pathogenesis and host interactions.IMPORTANCE During virus-induced leukemogenesis, ecotropic mouse leukemia viruses (MLVs) recombine with nonecotropic endogenous retroviruses (ERVs) to produce polytropic MLVs (P-MLVs). Analysis of 16 P-MLV genomes identified two segments consistently replaced: one at the envelope N terminus that alters receptor choice and one in the R peptide at the envelope C terminus, which is removed during virus assembly. Genome-wide analysis shows that nonecotropic replacements in the progenitor ecotropic MLV genome are more extensive than previously appreciated, covering 100% of the genome; contributions from xenotropic and polytropic ERVs differentially alter the regions responsible for receptor determination or subject to APOBEC3 and Fv1 restriction. All pathogenic viruses had modifications in the regulatory elements in their long terminal repeats and differed in a helical segment of envelope involved in entry and targeted by the host immune system. Virus-induced leukemogenesis thus involves generation of complex recombinants, and specific replacements are linked to pathogenesis and host restrictions.


Asunto(s)
Especificidad del Huésped/genética , Virus de la Leucemia Murina/clasificación , Virus de la Leucemia Murina/patogenicidad , Leucemia Experimental/virología , Infecciones por Retroviridae/virología , Infecciones Tumorales por Virus/virología , Proteínas Virales/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Evolución Molecular , Genoma Viral , Virus de la Leucemia Murina/genética , Ratones , Simulación de Dinámica Molecular , Conformación Proteica , Receptores Virales/genética , Receptores Virales/metabolismo , Homología de Secuencia , Secuencias Repetidas Terminales , Proteínas Virales/química , Proteínas Virales/metabolismo
16.
Nature ; 543(7646): 559-563, 2017 03 23.
Artículo en Inglés | MEDLINE | ID: mdl-28289286

RESUMEN

Highly potent and broadly neutralizing anti-HIV-1 antibodies (bNAbs) have been used to prevent and treat lentivirus infections in humanized mice, macaques, and humans. In immunotherapy experiments, administration of bNAbs to chronically infected animals transiently suppresses virus replication, which invariably returns to pre-treatment levels and results in progression to clinical disease. Here we show that early administration of bNAbs in a macaque simian/human immunodeficiency virus (SHIV) model is associated with very low levels of persistent viraemia, which leads to the establishment of T-cell immunity and resultant long-term infection control. Animals challenged with SHIVAD8-EO by mucosal or intravenous routes received a single 2-week course of two potent passively transferred bNAbs (3BNC117 and 10-1074 (refs 13, 14)). Viraemia remained undetectable for 56-177 days, depending on bNAb half-life in vivo. Moreover, in the 13 treated monkeys, plasma virus loads subsequently declined to undetectable levels in 6 controller macaques. Four additional animals maintained their counts of T cells carrying the CD4 antigen (CD4+) and very low levels of viraemia persisted for over 2 years. The frequency of cells carrying replication-competent virus was less than 1 per 106 circulating CD4+ T cells in the six controller macaques. Infusion of a T-cell-depleting anti-CD8ß monoclonal antibody to the controller animals led to a specific decline in levels of CD8+ T cells and the rapid reappearance of plasma viraemia. In contrast, macaques treated for 15 weeks with combination anti-retroviral therapy, beginning on day 3 after infection, experienced sustained rebound plasma viraemia when treatment was interrupted. Our results show that passive immunotherapy during acute SHIV infection differs from combination anti-retroviral therapy in that it facilitates the emergence of potent CD8+ T-cell immunity able to durably suppress virus replication.


Asunto(s)
Infecciones por VIH/inmunología , Infecciones por VIH/terapia , VIH/inmunología , Inmunización Pasiva , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/terapia , Virus de la Inmunodeficiencia de los Simios/inmunología , Animales , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/uso terapéutico , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Terapia Combinada , Modelos Animales de Enfermedad , Femenino , VIH/efectos de los fármacos , VIH/aislamiento & purificación , Anticuerpos Anti-VIH/administración & dosificación , Anticuerpos Anti-VIH/inmunología , Anticuerpos Anti-VIH/uso terapéutico , Infecciones por VIH/virología , Semivida , Macaca mulatta , Masculino , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacos , Virus de la Inmunodeficiencia de los Simios/aislamiento & purificación , Carga Viral/efectos de los fármacos , Carga Viral/inmunología , Viremia/inmunología , Viremia/terapia , Replicación Viral/efectos de los fármacos , Replicación Viral/inmunología
17.
Virology ; 504: 1-11, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-28131088

RESUMEN

APOBEC3G (A3G) is a cytidine deaminase with potent antiviral activity that is antagonized by Vif. A3G is expressed in a cell type-specific manner and some semi-permissive cells, including A3.01, express A3G but fail to block replication of Vif-null HIV-1. Here we explored the semi-permissive nature of A3.01 cells and found it to be defined exclusively by the levels of A3G. Indeed, minor changes in A3G levels rendered A3.01 cells either fully permissive or non-permissive for Vif-null HIV-1. Our data indicate that A3.01 cells express sub-lethal levels of catalytically active A3G that affects Vif-null HIV-1 at the proviral level but does not completely block virus replication due to purifying selection. Attempts to use the selective pressure exerted by such sub-lethal levels of A3G to select for APOBEC-resistant Vif-null virus capable of replicating in H9 cells failed despite passaging virus for five months, demonstrating that Vif is a critical viral accessory protein.


Asunto(s)
Desaminasa APOBEC-3G/genética , Linfocitos T CD4-Positivos/virología , Provirus/crecimiento & desarrollo , Replicación Viral/genética , Productos del Gen vif del Virus de la Inmunodeficiencia Humana/metabolismo , Desaminasa APOBEC-3G/antagonistas & inhibidores , Desaminasa APOBEC-3G/metabolismo , Secuencia de Bases , Línea Celular Tumoral , Preescolar , Femenino , Células HEK293 , Infecciones por VIH/virología , VIH-1/genética , Células HeLa , Humanos , Células Jurkat , Provirus/genética , Interferencia de ARN , ARN Interferente Pequeño/genética , ARN Viral/genética , Análisis de Secuencia de ARN , Productos del Gen vif del Virus de la Inmunodeficiencia Humana/genética
18.
J Virol ; 90(24): 11087-11095, 2016 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-27681142

RESUMEN

TRIM5α polymorphism limits and complicates the use of simian immunodeficiency virus (SIV) for evaluation of human immunodeficiency virus (HIV) vaccine strategies in rhesus macaques. We previously reported that the TRIM5α-sensitive SIV from sooty mangabeys (SIVsm) clone SIVsmE543-3 acquired amino acid substitutions in the capsid that overcame TRIM5α restriction when it was passaged in rhesus macaques expressing restrictive TRIM5α alleles. Here we generated TRIM5α-resistant clones of the related SIVsmE660 strain without animal passage by introducing the same amino acid capsid substitutions. We evaluated one of the variants in rhesus macaques expressing permissive and restrictive TRIM5α alleles. The SIVsmE660 variant infected and replicated in macaques with restrictive TRIM5α genotypes as efficiently as in macaques with permissive TRIM5α genotypes. These results demonstrated that mutations in the SIV capsid can confer SIV resistance to TRIM5α restriction without animal passage, suggesting an applicable method to generate more diverse SIV strains for HIV vaccine studies. IMPORTANCE: Many strains of SIV from sooty mangabey monkeys are susceptible to resistance by common rhesus macaque TRIM5α alleles and result in reduced virus acquisition and replication in macaques that express these restrictive alleles. We previously observed that spontaneous variations in the capsid gene were associated with improved replication in macaques, and the introduction of two amino acid changes in the capsid transfers this improved replication to the parent clone. In the present study, we introduced these mutations into a related but distinct strain of SIV that is commonly used for challenge studies for vaccine trials. These mutations also improved the replication of this strain in macaques with the restrictive TRIM5α genotype and thus will eliminate the confounding effects of TRIM5α in vaccine studies.


Asunto(s)
Cápside/inmunología , Proteínas Portadoras/genética , Evasión Inmune , ARN Viral/genética , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/inmunología , Alelos , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Animales , Cápside/química , Proteínas Portadoras/inmunología , Cercocebus atys , Femenino , Regulación de la Expresión Génica , Humanos , Masculino , Mutación , ARN Viral/inmunología , Alineación de Secuencia , Transducción de Señal , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/mortalidad , Síndrome de Inmunodeficiencia Adquirida del Simio/transmisión , Virus de la Inmunodeficiencia de los Simios/genética , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Análisis de Supervivencia , Dedos de Zinc
19.
J Clin Invest ; 126(6): 2295-307, 2016 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-27159392

RESUMEN

Current antiretroviral therapy (ART) is not sufficient to completely suppress disease progression in the CNS, as indicated by the rising incidence of HIV-1-associated neurocognitive disorders (HAND) among infected individuals on ART. It is not clear why some HIV-1-infected patients develop HAND, despite effective repression of viral replication in the circulation. SIV-infected nonhuman primate models are widely used to dissect the mechanisms of viral pathogenesis in the CNS. Here, we identified 4 amino acid substitutions in the cytoplasmic tail of viral envelope glycoprotein gp41 of the neurovirulent virus SIVsm804E that enhance replication in macrophages and associate with enhanced antagonism of the host restriction factor BM stromal cell antigen 2 (BST-2). Rhesus macaques were inoculated with a variant of the parental virus SIVsmE543-3 that had been engineered to contain the 4 amino acid substitutions present in gp41 of SIVsm804E. Compared with WT virus-infected controls, animals infected with mutant virus exhibited higher viral load in cerebrospinal fluid. Together, these results are consistent with a potential role for BST-2 in the CNS microenvironment and suggest that BST-2 antagonists may serve as a possible target for countermeasures against HAND.


Asunto(s)
Virus de la Inmunodeficiencia de los Simios/patogenicidad , Complejo SIDA Demencia/etiología , Sustitución de Aminoácidos , Animales , Antígenos CD/fisiología , Modelos Animales de Enfermedad , Proteínas Ligadas a GPI/antagonistas & inhibidores , Proteínas Ligadas a GPI/fisiología , VIH-1 , Interacciones Huésped-Patógeno , Humanos , Macaca mulatta , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/fisiología , Proteínas de los Retroviridae/genética , Proteínas de los Retroviridae/fisiología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/genética , Virus de la Inmunodeficiencia de los Simios/fisiología , Carga Viral , Virulencia/genética , Replicación Viral/genética
20.
Nature ; 533(7601): 105-109, 2016 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-27120156

RESUMEN

Despite the success of potent anti-retroviral drugs in controlling human immunodeficiency virus type 1 (HIV-1) infection, little progress has been made in generating an effective HIV-1 vaccine. Although passive transfer of anti-HIV-1 broadly neutralizing antibodies can protect mice or macaques against a single high-dose challenge with HIV or simian/human (SIV/HIV) chimaeric viruses (SHIVs) respectively, the long-term efficacy of a passive antibody transfer approach for HIV-1 has not been examined. Here we show, on the basis of the relatively long-term protection conferred by hepatitis A immune globulin, the efficacy of a single injection (20 mg kg(-1)) of four anti-HIV-1-neutralizing monoclonal antibodies (VRC01, VRC01-LS, 3BNC117, and 10-1074 (refs 9 - 12)) in blocking repeated weekly low-dose virus challenges of the clade B SHIVAD8. Compared with control animals, which required two to six challenges (median = 3) for infection, a single broadly neutralizing antibody infusion prevented virus acquisition for up to 23 weekly challenges. This effect depended on antibody potency and half-life. The highest levels of plasma-neutralizing activity and, correspondingly, the longest protection were found in monkeys administered the more potent antibodies 3BNC117 and 10-1074 (median = 13 and 12.5 weeks, respectively). VRC01, which showed lower plasma-neutralizing activity, protected for a shorter time (median = 8 weeks). The introduction of a mutation that extends antibody half-life into the crystallizable fragment (Fc) domain of VRC01 increased median protection from 8 to 14.5 weeks. If administered to populations at high risk of HIV-1 transmission, such an immunoprophylaxis regimen could have a major impact on virus transmission.


Asunto(s)
Anticuerpos Anti-VIH/administración & dosificación , Anticuerpos Anti-VIH/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Virus de la Inmunodeficiencia de los Simios/inmunología , Vacunas contra el SIDA/administración & dosificación , Vacunas contra el SIDA/inmunología , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/sangre , Anticuerpos Monoclonales/genética , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/genética , Anticuerpos Neutralizantes/inmunología , Femenino , Anticuerpos Anti-VIH/sangre , Anticuerpos Anti-VIH/genética , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , Infecciones por VIH/transmisión , Semivida , Fragmentos Fc de Inmunoglobulinas/química , Fragmentos Fc de Inmunoglobulinas/genética , Fragmentos Fc de Inmunoglobulinas/inmunología , Macaca mulatta/inmunología , Macaca mulatta/virología , Masculino , Mutación/genética , Estructura Terciaria de Proteína , Vacunas contra el SIDAS/administración & dosificación , Vacunas contra el SIDAS/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/sangre , Factores de Tiempo
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