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Climate change is affecting the phenology of organisms and ecosystem processes across a wide range of environments. However, the links between organismal and ecosystem process change in complex communities remain uncertain. In snow-dominated watersheds, snowmelt in the spring and early summer, followed by a long low-flow period, characterizes the natural flow regime of streams and rivers. Here, we examined how earlier snowmelt will alter the phenology of mountain stream organisms and ecosystem processes via an outdoor mesocosm experiment in stream channels in the Eastern Sierra Nevada, California. The low-flow treatment, simulating a 3- to 6-wk earlier return to summer baseflow conditions projected under climate change scenarios in the region, increased water temperature and reduced biofilm production to respiration ratios by 32%. Additionally, most of the invertebrate species explaining community change (56% and 67% of the benthic and emergent taxa, respectively), changed in phenology as a consequence of the low-flow treatment. Further, emergent flux pulses of the dominant insect group (Chironomidae) almost doubled in magnitude, benefitting a generalist riparian predator. Changes in both invertebrate community structure (composition) and functioning (production) were mostly fine-scale, and response diversity at the community level stabilized seasonally aggregated responses. Our study illustrates how climate change in vulnerable mountain streams at the rain-to-snow transition is poised to alter the dynamics of stream food webs via fine-scale changes in phenology-leading to novel predator-prey "matches" or "mismatches" even when community structure and ecosystem processes appear stable at the annual scale.
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Cambio Climático , Ecosistema , Animales , Ríos , Temperatura , Invertebrados , Estaciones del AñoRESUMEN
PURPOSE: Center volume is associated with improved survival after isolated heart transplant, but its impact on multiorgan heart transplant (MHT) outcomes is unknown. This study examines the impact of institutional MHT volume on MHT outcomes. METHODS: Adult patients undergoing first time MHT from 2011 to 2021 were identified in the United Network for Organ Sharing database. Transplant centers were annually classified as low-, medium-, or high-volume if they performed <3, 3 to 5, or ≥6 MHTs that year, respectively. Graft failure was defined as death, failure, or re-transplantation of any allograft. RESULTS: A total of 1860 MHTs were performed at 104 centers, including 482 (26%) at low-, 601 (32%) at medium-, and 777 (42%) at high-MHT volume centers. Noncardiac allografts included kidney (83%), liver (16%), and lung (2%). The proportion of MHTs performed at high-volume centers increased from 10% in 2011 to 62% in 2021. Recipient age, race, and body mass index did not vary by center volume (all P > .05). Patients at high-volume centers were more likely to be in the intensive care unit pre-transplant (58% vs 44%, P < .001) and have shorter waitlist times (47 vs 92 days, P < .001) than those at low-volume centers. 30-day graft survival was higher in combined medium- and high-volume compared with low-volume centers (95% vs 92%, P = .004). Increasing center MHT volume was protective against 30-day graft failure (adjusted hazard ratio 0.93 [0.88-0.98]) on multivariate Cox regression. CONCLUSIONS: Higher MHT volume is associated with improved early graft survival after MHT, which may justify centralizing the performance of MHTs to high-volume centers.
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Trasplante de Corazón , Trasplante de Riñón , Adulto , Humanos , Resultado del Tratamiento , Estudios Retrospectivos , Trasplante Homólogo , Supervivencia de Injerto , Trasplante de Corazón/efectos adversosRESUMEN
Temporary mechanical circulatory support (tMCS) is increasingly used for patients awaiting heart transplantation. Although examples of systemic inequity in cardiac care have been described, biases in tMCS use are not well characterized. This study explores the racial disparities in tMCS use and waitlist outcomes. The United Network for Organ Sharing database was used to identify adults listed for first-time heart transplantation from 2015 to 2021. White and non-White patients on extracorporeal membrane oxygenation, intra-aortic balloon pump, or temporary left ventricular assist device were identified. Waitlist outcomes of mortality, transplantation, and delisting were analyzed by race using competing risks regression. The effect of the new heart allocation system was also assessed. A total of 16,811 patients were included in this study, with 10,377 self-identifying as White and 6,434 as non-White. White patients were more often male, privately ensured, and had less co-morbidities (p <0.05). tMCS use was found to be significantly higher in non-White patients (p <0.001). Among those on tMCS, non-White patients were more likely to be delisted because of illness (subhazard ratio 1.34 [1.09 to 1.63]) and less likely to die while on the waitlist (subhazard ratio 0.76 [0.61 to 0.93]). This disparity was not present before the implementation of the new heart allocation system. tMCS use was proportional to the risk factors identified in the non-White cohort. After the implementation of the new heart allocation system, White patients were more likely to die, whereas non-White patients were more likely to be delisted. Further work is needed to determine the causes of and potential solutions for disparities in the waitlist outcomes.
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Oxigenación por Membrana Extracorpórea , Insuficiencia Cardíaca , Trasplante de Corazón , Corazón Auxiliar , Adulto , Humanos , Masculino , Factores Raciales , Resultado del Tratamiento , Factores de Riesgo , Listas de Espera , Insuficiencia Cardíaca/cirugía , Estudios RetrospectivosRESUMEN
BACKGROUND: Patients with renal disease on dialysis have significant comorbidity limiting life expectancy; however, these patients may experience accelerated prosthetic valve degeneration. The purpose of this study was to examine the impact of prosthesis choice on outcomes in dialysis patients undergoing mitral valve replacement (MVR) at our high-volume academic center. METHODS: Adults undergoing MVR were retrospectively reviewed between January 2002 and November 2019. Patients were included if they had documented renal failure and dialysis requirements before presentation. Patients were stratified by mechanical vs bioprosthetic prosthesis. Death and recurrent severe valve failure (3+ or greater) or redo mitral operation were used as primary outcomes. RESULTS: There were 177 dialysis patients identified who underwent MVR. Of these, 118 (66.7%) received bioprosthetic valves, whereas 59 (33.3%) received mechanical valves. Those who received mechanical valves were younger (48 vs 61 years; P < .001) and had less diabetes (32% vs 51%; P = .019). Prevalence of endocarditis and atrial fibrillation was similar. Postoperative length of stay was not different between groups. Risk-adjusted hazard for 5-year mortality was similar between groups (P = .668). Early mortality was high, with both groups having <50% actuarial survival at 2 years. No differences were noted in rates of structural valve deterioration or reintervention. More stroke events were noted on follow-up in patients receiving mechanical valves (15% vs 6%; P = .041). Endocarditis was the leading reason for reintervention; 4 patients received repeated surgery for bioprosthetic valve failure. CONCLUSIONS: MVR in dialysis patients carries significant morbidity and increased midterm mortality. Decreased life expectancy should be considered in the tailoring of prosthesis choice to dialysis-dependent patients.
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BACKGROUND: Demand for donor hearts and lungs exceeds their supply. Extended Criteria Donor (ECD) organs are used to help meet this demand, but their impact on heart-lung transplantation outcomes is poorly characterized. METHODS AND RESULTS: The United Network for Organ Sharing was queried for data on adult heart-lung transplantation recipients (n = 447) from 2005â2021. Recipients were stratified based on whether they received ECD hearts and/or lungs. Morbidity was analyzed using Kruskal-Wallis, chi-square, and Fisher's exact tests. Mortality was analyzed using Kaplan-Meier estimation, log-rank tests and Cox regression. Sixty-five (14.5%) patients received two ECD organs, 134 (30.0%) received only an ECD lung, and 65 (14.5%) only an ECD heart. Recipients of two ECD organs were older, more likely to have diabetes, and more likely transplanted from 2015â2021 (p < 0.05). Groups did not differ by pre-transplant diagnosis, intensive care unit disposition, life support use, or hemodynamics. Group five-year survival rates ranged from 54.5% to 63.2% (p = 0.428). Groups did not differ by 30-day mortality, strokes, graft rejection, or hospital length of stay. CONCLUSIONS: Using ECD hearts and/or lungs for heart-lung transplantation is not associated with increased mortality and is a safe strategy for increasing donor organ supply in this complex patient population.
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Trasplante de Corazón , Trasplante de Corazón-Pulmón , Obtención de Tejidos y Órganos , Adulto , Humanos , Donantes de Tejidos , Pulmón , Estudios Retrospectivos , Supervivencia de InjertoRESUMEN
BACKGROUND: In October 2018, the United States implemented a change in the donor heart allocation policy from a three-tiered to a six-tiered status system. The purpose of the current study was to examine changes in waitlist patterns among patients listed for concomitant heart-liver transplantation with implementation of the new allocation system. METHODS: Patients listed for heart-liver transplantation between January 1, 2012, and June 30, 2021, were identified from the United Network for Organ Sharing database. Patients were grouped by era according to initial list date before or after October 18, 2018. Competing risks regression for mortality, transplantation, removal from waitlist due to illness was performed according to the method of Fine and Gray. Waitlist data were censored at 3 years from initial listing. RESULTS: Overall, 523 patients were identified, of whom 310 were listed before (era 1, 59%) and 213 after (era 2, 41%) allocation change. Patients in era 1 were older, had more restrictive cardiomyopathy, and more preoperative inotrope use (all P < .05). However, patients in era 2 has longer ischemic times (3.5 ± 1.1 vs 3.1 ± 1.1 hours, P < .01) and more intraaortic balloon pump use (8.9% vs 3.9%, P = .016). Era 2 was associated with lower subdistribution hazard for death (hazard ratio 0.37; 95% CI, 0.13-1.02; P = .054) and increased transplantation (hazard ratio 1.35; 95% CI, 1.06-1.72; P = .015). CONCLUSIONS: The implementation of the US donor heart allocation policy was associated with more preoperative intraaortic balloon pump use for patients listed for heart-liver transplantation. Despite that, the modern era was associated with lower waitlist mortality and more frequent transplantation, without increased risk of delisting due to illness.
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Trasplante de Corazón , Trasplante de Hígado , Obtención de Tejidos y Órganos , Humanos , Estados Unidos/epidemiología , Trasplante de Corazón/métodos , Donantes de Tejidos , Modelos de Riesgos Proporcionales , Listas de Espera , Estudios RetrospectivosRESUMEN
Objective: The choice to operate on moderate tricuspid regurgitation (TR) during mitral surgery is challenging owing to limited mid-term data. We assess whether concomitant tricuspid operations improve mid-term quality of life, morbidity, or mortality. Methods: An institutional database identified mitral surgery recipients with moderate TR at the time of surgery from 2010 to 2019. Patients were stratified by the presence of a concomitant tricuspid operation. Quality of life at the last follow-up was assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Morbidity was compared using the χ2 test, Mann-Whitney U test, and Student t test. Survival was analyzed with Kaplan-Meier estimation. Results: Of 210 mitral surgery recipients, 67 (31.9%) underwent concomitant tricuspid surgery. The concomitant tricuspid surgery cohort had greater preoperative dialysis use (10.5% vs 3.5%; P = .043) but similar age, New York Heart Association class, and cardiac surgery history relative to the nonconcomitant cohort (P > .05 for all). The concomitant tricuspid surgery cohort had a longer cardiopulmonary bypass time (144 minutes vs 122 minutes; P = .005) but a similar rate of mitral repair (P = .220). Postoperative KCCQ-12 scores reflected high quality of life in both cohorts (95.1 vs 89.1; P = .167). The concomitant tricuspid surgery cohort trended toward a higher perioperative pacemaker placement rate (22.8% vs 12.7%; P = .088) but were less likely to develop severe TR (0.0% vs 13.0%; P = .004). Overall survival was comparable between the 2 cohorts at 1 year (84.9% vs 81.6%; P = .628) and 5 years (73.5% vs 57.9%; P = .078). Five-year survival free from severe TR was higher in the concomitant cohort (73.5% vs 54.3%; P = .032). Conclusions: Concomitant tricuspid surgery for moderate TR is associated with increased 5-year survival free from severe TR but not with increased quality of life.
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Abstract Background: Demand for donor hearts and lungs exceeds their supply. Extended Criteria Donor (ECD) organs are used to help meet this demand, but their impact on heart-lung transplantation outcomes is poorly characterized. Methods and results: The United Network for Organ Sharing was queried for data on adult heart-lung transplantation recipients (n = 447) from 2005‒2021. Recipients were stratified based on whether they received ECD hearts and/or lungs. Morbidity was analyzed using Kruskal-Wallis, chi-square, and Fisher's exact tests. Mortality was analyzed using Kaplan-Meier estimation, log-rank tests and Cox regression. Sixty-five (14.5%) patients received two ECD organs, 134 (30.0%) received only an ECD lung, and 65 (14.5%) only an ECD heart. Recipients of two ECD organs were older, more likely to have diabetes, and more likely transplanted from 2015‒2021 (p < 0.05). Groups did not differ by pre-transplant diagnosis, intensive care unit disposition, life support use, or hemodynam-ics. Group five-year survival rates ranged from 54.5% to 63.2% (p = 0.428). Groups did not differ by 30-day mortality, strokes, graft rejection, or hospital length of stay. Conclusions: Using ECD hearts and/or lungs for heart-lung transplantation is not associated with increased mortality and is a safe strategy for increasing donor organ supply in this complex patient population.
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OBJECTIVES: The decision to perform simultaneous heart-kidney transplant (HKT) rather than isolated heart transplant (IHT) for patients with advanced kidney disease is challenging. Limited data exist to guide this decision in obese patients. We sought to compare mortality after HKT and IHT in obese patients with non-dialysis-dependent kidney disease. METHODS: The United Network for Organ Sharing was queried for data on adult heart transplant recipients from 2000 to 2022. Inclusion criteria were obesity, estimated glomerular filtration rate <45 ml/min/1.73 m2 and no pretransplant dialysis. HKT and IHT recipients were propensity matched. Morbidity was compared using chi-squared, Fisher's exact and McNemar's tests. Survival was assessed with Kaplan-Meier estimation. Risk factors for mortality were examined with Cox regression. RESULTS: A total of 289 HKT and 1920 IHT recipients met inclusion criteria. Heart-kidney recipients had higher baseline creatinine and rates of intensive care unit disposition than IHT recipients (both standardized mean differences >0.10). Propensity matching resulted in 239 pairs of HKT and IHT recipients with minimal differences in baseline characteristics. Heart-kidney recipients had higher 5- and 10-year survival than IHT recipients on unmatched (77% vs 69%, P = 0.011 and 58% vs 48%, P = 0.008) and propensity matched analyses (77% vs 68%, P = 0.026 and 57% vs 39%, P = 0.007). Heart-kidney transplantation was protective against 10-year mortality on multivariable regression (hazard ratio 0.585, P = 0.002). CONCLUSIONS: In obese patients with non-dialysis-dependent kidney disease, HKT may decrease long-term mortality relative to IHT and should be strongly considered as a preferred treatment.
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Insuficiencia Cardíaca , Trasplante de Corazón , Trasplante de Riñón , Adulto , Humanos , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/métodos , Riñón , Obesidad/complicaciones , Obesidad/cirugía , Estudios RetrospectivosRESUMEN
Left ventricular assist devices (LVADs) improve survival and quality of life for patients with advanced heart failure but are associated with high rates of thromboembolic and hemorrhagic complications. Antithrombotic therapy is required following LVAD implantation, though practices vary. Identifying a therapeutic strategy that minimizes the risks of thromboembolic and hemorrhagic complications is critical to optimizing patient outcomes and is an area of active investigation. This paper reviews strategies for initiating and maintaining antithrombotic therapy in durable LVAD recipients, focusing on those with centrifugal-flow devices.
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OBJECTIVES: Early graft failure (EGF) is a devastating postoperative complication following heart transplant. Institutional studies have modelled donor and recipient risk factors predictive of graft failure. To date, no studies have assessed specific recipient profiles associated with mortality after recipients suffer from EGF. The objective of this study was to identify this recipient profile. METHODS: We performed a retrospective review of patients in the United Network for Organ Sharing database undergoing heart transplant from August 2000 to September 2019. EGF was defined as graft dysfunction at 24 hours post-heart transplant. The primary outcome was 90-day mortality. To isolate recipient characteristics associated with mortality, we performed the univariate analysis on 24 recipient characteristics adjusted for high-risk donor characteristics (ischaemic time, donor age, race mismatch, BUN/creatinine ratio) predictive of 1-year mortality (P < 0.2). We then performed backward stepwise multivariable regression adjusted for identified donor characteristics to determine recipient characteristics associated with mortality after EGF (P < 0.05). RESULTS: We identified 302 patients diagnosed with post-transplant EGF. Among these patients, mortality was 82% within 90 days of transplantation. Adjusted univariate analysis identified 7 factors associated with mortality. Adjusted backward stepwise multivariable regression identified BMI > 30 as predictive of mortality at 90 days after EGF. CONCLUSIONS: Patients who develop EGF after heart transplant are at high risk for mortality. Careful discussion regarding transplant candidacy and risk is warranted in obese patients. In addition, minimizing donor factors associated with graft dysfunction is critical during preoperative planning in these recipients.
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Supervivencia de Injerto , Trasplante de Corazón , Factor de Crecimiento Epidérmico , Humanos , Obesidad , Estudios Retrospectivos , Factores de Riesgo , Donantes de Tejidos , Resultado del TratamientoRESUMEN
Mountains are global biodiversity hotspots where cold environments and their associated ecological communities are threatened by climate warming. Considerable research attention has been devoted to understanding the ecological effects of alpine glacier and snowfield recession. However, much less attention has been given to identifying climate refugia in mountain ecosystems where present-day environmental conditions will be maintained, at least in the near-term, as other habitats change. Around the world, montane communities of microbes, animals, and plants live on, adjacent to, and downstream of rock glaciers and related cold rocky landforms (CRL). These geomorphological features have been overlooked in the ecological literature despite being extremely common in mountain ranges worldwide with a propensity to support cold and stable habitats for aquatic and terrestrial biodiversity. CRLs are less responsive to atmospheric warming than alpine glaciers and snowfields due to the insulating nature and thermal inertia of their debris cover paired with their internal ventilation patterns. Thus, CRLs are likely to remain on the landscape after adjacent glaciers and snowfields have melted, thereby providing longer-term cold habitat for biodiversity living on and downstream of them. Here, we show that CRLs will likely act as key climate refugia for terrestrial and aquatic biodiversity in mountain ecosystems, offer guidelines for incorporating CRLs into conservation practices, and identify areas for future research.
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Ecosistema , Cubierta de Hielo , Animales , Biodiversidad , Clima , Cambio Climático , Refugio de FaunaRESUMEN
Monitoring of benthic invertebrates in streams receiving acidic metal-contaminated water over an 18-yr period revealed both degraded conditions and recovery along a network of downstream locations. Compared with reference streams, and over the course of clean-up remediation efforts below an abandoned open-pit sulfur mine in the central Sierra Nevada of California, improving water quality was accompanied by recovery of benthic communities at some sites. Years of high flow resulted in degraded biological status when acid mine drainage capture was incomplete and metal loading had increased with runoff. Seasonal patterns of recovery evident in the fall after the summer treatment season reverted in the next spring after overwinter periods when sources were not captured. As the metal load has been reduced, phased recovery of community structure, function, and similarity progressed toward that of reference assemblage taxonomic composition. From impacted communities dominated by relatively tolerant midges, reassembly involved an increase in density, return of long-lived taxa, an increased ratio of sensitive-to-tolerant forms, then overall diversity and community composition, and eventually large predators and grazers reappearing along with mayfly, stonefly, and caddisfly richness. Threshold effect levels defined using several analysis methods showed that the response range of biological indicators corresponds to US Environmental Protection Agency guidelines of predicted effects utilizing cumulative criterion units (CCUs) of metal toxicity (i.e., CCU â¼ 1). All sites have shown improved function with increased density of some or all trophic groups over time. Although recovery is progressing, year-around treatment may be necessary to fully restore biological integrity in streams nearest the mine. Environ Toxicol Chem 2018;37:2575-2592. © 2018 SETAC.
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Ácidos/química , Monitoreo del Ambiente , Invertebrados/efectos de los fármacos , Metales/toxicidad , Minería , Contaminantes Químicos del Agua/toxicidad , Animales , California , Chironomidae/efectos de los fármacos , Ephemeroptera/efectos de los fármacos , Geografía , Insectos/efectos de los fármacos , Invertebrados/fisiología , Nevada , Factores de TiempoAsunto(s)
Anticuerpos Antivirales/sangre , Virus de la Hepatitis E/inmunología , Hepatitis E/diagnóstico , ARN Viral/sangre , Ribavirina/uso terapéutico , Adulto , Enfermedad Crónica , Hepatitis E/tratamiento farmacológico , Virus de la Hepatitis E/genética , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Trasplante de Riñón , Masculino , Ribavirina/efectos adversos , Estados UnidosRESUMEN
INTRODUCTION: Chronic hepatitis C virus (HCV) infection is ubiquitous, affecting approximately 180 million individuals worldwide and around 3.2 million in the United States. While peginterferon and ribavirin alone continue to be used, the treatment landscape for patients with genotype 1 has recently changed to include one of two protease inhibitors: boceprevir and telaprevir. Despite this, effective therapies for chronic HCV for all genotypes represent a largely unmet need. AREAS COVERED: Sofosbuvir , formally labeled GS-7977, is an HCV NS5B nucleotide polymerase inhibitor that has entered multiple Phase III trials. Phase II trials demonstrated that treatments including sofosbuvir have higher sustained virologic response rates for genotypes 1, 2, 3, 4 and 6 in comparison with treatments that include only peginterferon and ribavirin. In addition, the side-effect profile of sofosbuvir and ribavirin dual treatment has an improved tolerability in comparison with treatment regimes that include interferon-based options. EXPERT OPINION: The hope and expectation is that interferon is eliminated from the armamentarium of HCV therapy and that all-oral therapies prove effective although interferon in combination with multiple drugs may still be required to treat select patients. In addition, there is a need to develop effective therapies for all HCV genotypes with simple and well-tolerated regimes.
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Antivirales/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Uridina Monofosfato/análogos & derivados , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/farmacología , Inhibidores Enzimáticos/farmacología , Humanos , Nucleotidiltransferasas/antagonistas & inhibidores , Sofosbuvir , Uridina Monofosfato/farmacología , Uridina Monofosfato/uso terapéuticoRESUMEN
To identify host proteins interacting with Tomato bushy stunt virus (TBSV) replication proteins in a genome-wide scale, we have used a yeast (Saccharomyces cerevisiae) proteome microarray carrying 4,088 purified proteins. This approach led to the identification of 58 yeast proteins that interacted with p33 replication protein. The identified host proteins included protein chaperones, ubiquitin-associated proteins, translation factors, RNA-modifying enzymes, and other proteins with yet-unknown functions. We confirmed that 19 of the identified host proteins bound to p33 in vitro or in a split-ubiquitin-based two-hybrid assay. Further analysis of Cdc34p E2 ubiquitin-conjugating enzyme, which is one of the host proteins interacting with p33, revealed that Cdc34p is a novel component of the purified viral replicase. Downregulation of Cdc34p expression in yeast, which supports replication of a TBSV replicon RNA (repRNA), reduced repRNA accumulation and the activity of the tombusvirus replicase by up to fivefold. Overexpression of wild-type Cdc34p, but not that of an E2-defective mutant of Cdc34p, increased repRNA accumulation, suggesting a significant role for the ubiquitin-conjugating enzyme function of Cdc34p in TBSV replication. Also, Cdc34p was able to ubiquitinate p33 in vitro. In addition, we have shown that p33 becomes ubiquitinated in vivo. We propose that ubiquitination of p33 likely alters its function or affects the recruitment of host factors during TBSV replication.
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Tombusvirus/fisiología , Complejos de Ubiquitina-Proteína Ligasa/metabolismo , Proteínas Virales/metabolismo , Replicación Viral/fisiología , Ciclosoma-Complejo Promotor de la Anafase , Análisis por Matrices de Proteínas , Unión Proteica , ARN Viral/metabolismo , ARN Polimerasa Dependiente del ARN/química , ARN Polimerasa Dependiente del ARN/aislamiento & purificación , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Técnicas del Sistema de Dos Híbridos , UbiquitinaciónRESUMEN
Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) can invade the central nervous system (CNS) during acute infection but virus replication is apparently controlled because clinical and pathological manifestations of CNS disease in HIV/SIV-infected individuals usually present later in infection, coincident with immunosuppression and acquired immuno-deficiency syndrome (AIDS). Using an established SIV/macaque model of HIV dementia, the authors recently demonstrated that acute virus replication is down-regulated (to undetectable viral RNA levels) in the brain, but not the periphery, as early as 21 days post inoculation (p.i.). Viral DNA levels in the brain remain constant, suggesting that infected cells persist in the CNS and that replication is inhibited largely at a transcriptional level. In vitro, active replication of HIV in macrophages can be inhibited by treatment with interferon (IFN)beta via a mechanism involving induction of a dominant-negative form of the transcription factor C/EBP (CCAAT/enhancer-binding protein)beta. Because macrophages are the primary cell types infected with HIV/SIV in the CNS and HIV replication in macrophages requires C/EBP sites within the viral long terminal repeat (LTR), the authors considered the possibility that suppression of C/EBP-dependent transcription contributes to the mechanism by which acute HIV/SIV replication is inhibited in the CNS. Here, the authors report that IFNbeta can also inhibit ongoing SIV replication in macaque macrophages in vitro. Further, the authors demonstrate that IFNbeta levels in the brain increase between 7 and 21 days p.i. in parallel with increased expression of the dominant-negative isoform of C/EBPbeta. These results suggest that innate immune responses involving IFNbeta may contribute to the mechanism(s) controlling acute SIV replication in the CNS.
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Encéfalo/virología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/crecimiento & desarrollo , Virus de la Inmunodeficiencia de los Simios/inmunología , Enfermedad Aguda , Animales , Antivirales/farmacología , Proteínas Potenciadoras de Unión a CCAAT/genética , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , ADN Viral/análisis , Expresión Génica/inmunología , Interferón beta/genética , Interferón beta/farmacología , Macaca mulatta , Macrófagos/virología , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacos , Factor de Transcripción CHOP , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
It is well accepted that viruses require access to specific intracellular environments in order to proliferate or, minimally, to secure future proliferative potential as latent reservoirs. Hence, identification of essential virus-cell interactions should both refine current models of virus replication and proffer alternative targets for therapeutic intervention. In the present study, we examined the activation states of mitogen-activated protein kinases (MAPKs), ERK-1/2, in primary cells susceptible to visna virus and report that virus infection induces and sustains activation of the ERK/MAPK pathway. Treatment of infected cells with PD98059, a specific inhibitor of the ERK/MAPK pathway, abolishes visna virus replication, as evidenced by extremely low levels of Gag protein expression and reverse transcriptase activity in culture supernatants. In addition, although visna virus-induced activation of MAPK is detectable within 15 min, early events of viral replication (i.e., reverse transcription, integration, and transcription) are largely unaffected by PD98059. Interestingly, further examination demonstrated that treatment with PD98059 results in decreased cytoplasmic expression of gag and env, but not rev, mRNA, highly suggestive of an ERK/MAPK-dependent defect in Rev function. In vivo analysis of ERK-1/2 activation in brains derived from visna virus-infected sheep demonstrates a strong correlation between ERK/MAPK activation and virus-associated encephalitis. Moreover, double-labeling experiments revealed that activation of MAPK occurs not only in cells classically infected by visna virus (i.e., macrophages and microglia), but also in astrocytes, cells not considered to be major targets of visna virus replication, suggesting that activation of the ERK/MAPK pathway may contribute to the virus-induced processes leading to neurodegenerative pathology.