Virulence and immunogenicity of blue catfish alloherpesvirus in channel, blue and blue × channel hybrid catfish.

Blue catfish alloherpesvirus (BCAHV) is a novel virus isolated from the blue catfish (Ictalurus furcatus). To date, the ultrastructure, virulence and immunogenicity of BCAHV have not been reported. Given the importance of blue catfish in producing channel ♀ (I. punctatus) × â™‚ blue (I. furcatus) catfish hybrids and the increasing demand for hybrid catfish in the US catfish industry, the susceptibility of blue, channel and hybrid catfish to BCAHV was assessed. Further, the cross-protective potential of BCAHV against Ictalurid herpesvirus 1 (IcHV1) was investigated in channel and hybrid catfish that survive BCAHV exposure. Neutralization assays revealed BCAHV is refractive (neutralization index [NI] = 0) to anti-IcHV1 monoclonal antibody Mab 95, compared to IcHV1 (NI = 1.8). Exposure of blue catfish fingerling to 1.3 × 105 TCID50 /L BCAHV produced cumulative mortality of 51.67 ± 0.70% and pathologic changes similar to those of channel catfish virus disease. No mortality was observed in channel or hybrid catfish. Twenty-eight days post-challenge, surviving channel and hybrid catfish were exposed to 9.4 × 104 TCID50 /L IcHV1 (LC50 dose), resulting in 100% relative per cent survival compared to naïve cohorts. These data provide baseline information for BCAHV and lay the groundwork for future studies. Data also identify BCAHV as a potential vaccine candidate against IcHV1. Based on host range and immunogenicity evaluations, in addition to genome sequence data from previous studies, BCAHV should be given consideration as a new species of Ictalurivirus.

First detection of Herpesvirus anguillae (AngHV-1) associated with mortalities in farmed giant mottled eel (Anguilla marmorata) in Vietnam.

Giant mottled eel (Anguilla marmorata) farming in Vietnam is a multistage process starting from wild harvest of glass eels through the so-called "hatcheries" and distribution centres from which individuals are transferred to rearing farms and subsequently sold by one eel farm to another every 3-5 months. The information on viral agents spread and persistence in the Vietnamese eel aquaculture is scarce. Therefore, the mortality of A. marmorata at the Van Xuan Farm was the prerequisite to identify the possible aetiologic agent and additionally to formulate first recommendations for viral disease screening in the Vietnamese eel aquaculture. Juvenile giant mottled eels with haemorrhagic lesions in the skin and liver, and hyperaemia of the gut were tested with qPCR and end-point PCR for AngHV-1 presence. Here, we report the first detection of AngHV-1 associated with mortality in giant mottled eel in winter and spring seasons. On the basis of the obtained results, we recommend to test eel seeds in "hatcheries," since tropical eel farms operate in interconnected scheme and monitoring of AngHV-1 prevalence requires well-implemented measures. Disease screening in the rearing centres and on-growing facilities should be based on everyday health checks, including by-catch fish used as a base of the feeding programmes at eel farms in Vietnam.

The Pacific Oyster Mortality Syndrome, a Polymicrobial and Multifactorial Disease: State of Knowledge and Future Directions.

The Pacific oyster (Crassostreae gigas) has been introduced from Asia to numerous countries around the world during the 20th century. C. gigas is the main oyster species farmed worldwide and represents more than 98% of oyster production. The severity of disease outbreaks that affect C. gigas, which primarily impact juvenile oysters, has increased dramatically since 2008. The most prevalent disease, Pacific oyster mortality syndrome (POMS), has become panzootic and represents a threat to the oyster industry. Recently, major steps towards understanding POMS have been achieved through integrative molecular approaches. These studies demonstrated that infection by Ostreid herpesvirus type 1 µVar (OsHV-1 µvar) is the first critical step in the infectious process and leads to an immunocompromised state by altering hemocyte physiology. This is followed by dysbiosis of the microbiota, which leads to a secondary colonization by opportunistic bacterial pathogens, which in turn results in oyster death. Host and environmental factors (e.g. oyster genetics and age, temperature, food availability, and microbiota) have been shown to influence POMS permissiveness. However, we still do not understand the mechanisms by which these different factors control disease expression. The present review discusses current knowledge of this polymicrobial and multifactorial disease process and explores the research avenues that must be investigated to fully elucidate the complexity of POMS. These discoveries will help in decision-making and will facilitate the development of tools and applied innovations for the sustainable and integrated management of oyster aquaculture.

Characterization of a Novel Alphaherpesvirus Isolated from the Fruit Bat Pteropus lylei in Vietnam.

Herpesviruses exist in nature within each host animal. Ten herpesviruses have been isolated from bats and their biological properties reported. A novel bat alphaherpesvirus, which we propose to name "Pteropus lylei-associated alphaherpesvirus (PLAHV)," was isolated from urine of the fruit bat Pteropus lylei in Vietnam and characterized. The entire genome sequence was determined to be 144,008 bp in length and predicted to include 72 genes. PLAHV was assigned to genus Simplexvirus with other bat alphaherpesviruses isolated from pteropodid bats in Southeast Asia and Africa. The replication capacity of PLAHV in several cells was evaluated in comparison with that of herpes simplex virus 1 (HSV-1). PLAHV replicated better in the bat-originated cell line and less in human embryonic lung fibroblasts than HSV-1 did. PLAHV was serologically related to another bat alphaherpesvirus, Pteropodid alphaherpesvirus 1 (PtAHV1), isolated from a Pteropus hypomelanus-related bat captured in Indonesia, but not with HSV-1. PLAHV caused lethal infection in mice. PLAHV was as susceptible to acyclovir as HSV-1 was. Characterization of this new member of bat alphaherpesviruses, PLAHV, expands the knowledge on bat-associated alphaherpesvirology.IMPORTANCE A novel bat alphaherpesvirus, Pteropus lylei-associated alphaherpesvirus (PLAHV), was isolated from urine of the fruit bat Pteropus lylei in Vietnam. The whole-genome sequence was determined and was predicted to include 72 open reading frames in the 144,008-bp genome. PLAHV is circulating in a species of fruit bats, Pteropus lylei, in Asia. This study expands the knowledge on bat-associated alphaherpesvirology.

Koi herpesvirus and carp oedema virus: Infections and coinfections during mortality events of wild common carp in the United States.

Koi herpesvirus (KHV; cyprinid herpesvirus-3) and carp oedema virus (CEV) are important viruses of common and koi carp (Cyprinus carpio); however, the distribution of these viruses in wild common carp in North America is largely unknown. During the summers of 2017 and 2018, 27 mass mortalities of common carp were reported from four states in the USA (Minnesota, Iowa, Pennsylvania and Wisconsin), the majority of which were distributed across eight major watersheds in southern Minnesota. Samples from 22 of these mortality events and from five clinically healthy nearby carp populations were screened for KHV, CEV and SVCV using real-time polymerase chain reaction (qPCR). KHV was confirmed in 13 mortality events, CEV in two mortality events and coinfections of KHV/CEV in four mortality events. Nucleotide sequence analysis revealed that the KHV and CEV detected here are closely related to European lineages of these viruses. While molecular detection alone cannot conclusively link either virus with disease, the cases described here expand the known range of two important viruses. This is also the first reported detection of KHV and CEV coinfections in wild carp populations.

Survival analysis of confirmed elephant endotheliotropic herpes virus cases in Thailand from 2006 - 2018.

The elephant endotheliotropic herpesvirus (EEHV) has been a known cause of death of young elephants in Thailand for over a decade. In this study, we report on the demography, disease characteristics and mortality of 58 elephants with confirmed EEHV hemorrhagic disease between January 2006 and August 2018 using retrospective data subjected to survival analysis. Median age of EEHV presentation was 29 months, and the mortality rate was 68.97% with a median survival time of 36 h. Most EEHV cases occurred in the north of Thailand, the region where most of the country's captive elephants reside. The hazard ratio analysis identified application of medical procedures and antiviral medications as being significant factors correlated to the risk of death. Our results indicate a need to focus EEHV monitoring efforts on young elephants and to follow current protocols that advise starting treatments before clinical signs appear.

Resurgence of Salmonid Herpesvirus-3 Infection (Epizootic Epitheliotropic Disease) in Hatchery-Propagated Lake Trout in Michigan.

Over the past century, populations of Lake Trout Salvelinus namaycush have declined throughout the Great Lakes basin due to overfishing, habitat destruction, introduction of invasive species, and associated recruitment issues from high thiaminase, as well as emerging infectious diseases. To combat these declines, state and federal fishery management agencies undertook substantial stock enhancement efforts, including more stringent regulation of sport and commercial catch limits and increasing hatchery propagation of Lake Trout stocked into Great Lakes basin waterways. One state fish hatchery involved in these rehabilitation efforts experienced mass mortality events in 2012 and 2017. In 2012, following a period of abnormally heavy rain, hatchery staff observed abnormal behavior followed by increased mortalities in two strains of Lake Trout fingerlings, reaching upwards of 20% mortality and totaling a loss of approximately 100,000 fish. In 2017, following another heavy-rain season, 6-8% of 2-year-old Lake Trout experienced morbidity and mortality similar to that observed in 2012. During the 2012 event, Brook Trout Salvelinus fontinalis and splake (Lake Trout × Brook Trout hybrid) reared in flow-through systems receiving water from diseased Lake Trout remained clinically unaffected. Molecular analyses revealed all lots of affected Lake Trout were infected with the salmonid herpesvirus-3 (epizootic epitheliotropic disease virus [EEDV]), a disease that caused complete depopulation of this hatchery in the late 1980s and until 2012 was never again detected in this hatchery or in Michigan. Further sampling detected EEDV in apparently healthy 5-year-old Lake Trout and in wild Mottled Sculpin Cottus bairdii collected in the hatchery source water. The ability of the virus to replicate in tissues of infected fish was verified by exposing naïve Lake Trout to the filtered tissue homogenates of infected fish resulting in similar disease signs. Despite the virus going undetected for many years, these two EEDV episodes clearly demonstrate the continued presence of this deadly herpesvirus in the Great Lakes basin.

Determination of risk factors for herpesvirus outbreak in oysters using a broad-scale spatial epidemiology framework.

Marine diseases have major impacts on ecosystems and economic consequences for aquaculture and fisheries. Understanding origin, spread and risk factors of disease is crucial for management, but data in the ocean are limited compared to the terrestrial environment. Here we investigated how the marine environment drives the spread of viral disease outbreak affecting The Pacific oyster worldwide by using a spatial epidemiology framework. We collected environmental and oyster health data at 46 sites spread over an area of 300 km2 along an inshore-offshore gradient during an epizootic event and conducted risk analysis. We found that disease broke out in the intertidal farming area and spread seaward. Mortalities and virus detection were observed in oysters placed 2 km from the farming areas, but oysters of almost all sites were subclinically infected. Increasing food quantity and quality, growth rate and energy reserves of oyster were associated with a lower risk of mortality offshore whereas increasing turbidity, a proxy of the concentration of suspended particulate matter, and terrestrial inputs, inferred from fatty acid composition of oysters, were associated with a higher risk of mortality. Offshore farming and maintenance of good ecological status of coastal waters are options to limit disease risk in oysters.

Risk factors for early viral infections after liver transplantation.

PURPOSE: Viral infections represent a serious threat for patients after liver transplantation (LT). The identification of risk factors during the early post-transplant period might help to improve prevention of viral infections after LT. METHODS: Between 2004 and 2010, 530 adult patients underwent LT at a large university hospital serving a metropolitan region in Europe. This retrospective single-centre study analysed putative risk factors for early viral infections with herpes simplex virus-1 (HSV-1), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), hepatitis A/B/C (HAV/HBV/HCV) and cytomegalovirus (CMV) in the first 3 months after LT. RESULTS: The final analysis included 501 patients of whom 126 (25.1%) had documented viral infections after LT. No significant differences could be detected between patients with or without viral infections concerning 30- and 90-day mortality. Risk factors in the early post-transplant period identified by multivariate analysis included female gender (CMV, HSV-1), the post-operative need for continuous veno-venous hemofiltration (CMV), septic shock (CMV), detection of fungi (CMV) and the intraoperative amount of transfused blood (EBV). CONCLUSIONS: Enhanced vigilance regarding opportunistic infections is crucial in the management of this high-risk population of immunocompromised patients. In particular, attention should be paid to avoidable conditions that increase the risk of renal replacement therapies in the post-LT setting, especially among women. TRIAL REGISTRATION: DRKS00010672 on German Clinical Trial Register.

Identificación de citomegalovirus y varicela zoster virus en lesiones cutáneas en una paciente con sida Presentación de un caso y revisión de la bibliografía / CENTRAL NERVOUS SYSTEM INVOLVEMENT DUE TO HERPESVIRUS REACTIVATION IN AIDS PATIENTS

Las reactivaciones de las infecciones latentes por virus de la familia Herpes originan variadas y graves manifestaciones clínicas en los enfermos con sida. Las lesiones mucocutáneas son comunes en las infecciones por Herpes simple 1 y 2 y por varicela-zóster (VZV). En cambio, son infrecuentes en infecciones por citomegalovirus (CMV). La coexistencia de más de un patógeno en la misma lesión ha sido escasamente referida en la literatura. Presentamos una paciente con enfermedad VIH/sida avanzada que desarrolló lesiones cutáneas diseminadas, en una de las cuales se identificó por técnica de PCR el genoma de VZV y CMV. El diagnóstico precoz seguido del tratamiento antiherpético y la reconstitución inmunológica alcanzada con la TARGA pueden mejorar el pronóstico de esta clase de pacientes

The reactivation of latent infections due to Herpesviridae is associated with a serious compromise in HIV/AIDS patients. Mucocutaneous lesions are frequent in disseminated infections due to Herpes simple 1 and 2 and varicella-zoster virus (VZV). However, cutaneous involvement is rare in cytomegalovirus infections. The coexistence of VZV and CMV in the same lesion has been little reported in the literature. Here, we describe a female with advanced HIV/AIDS disease who developed disseminated cutaneous lesions, in one of yhem we detected VZV and CMV by PCR. Early diagnosis followed by specific antiherpetic therapy and the immune reconstitution associated with HAART can improve the prognosis of these kind of patients.

Relapse of HHV8-positive multicentric Castleman disease following rituximab-based therapy in HIV-positive patients.

Successful treatment of HIV-associated multicentric Castleman disease (HIV+MCD) with rituximab-based approaches has dramatically improved survival and reduced the risk of human herpesvirus 8 (HHV8)-associated lymphoma. Longer term outcomes including relapse rates have not been described and are important to establish the potential role of maintenance therapy. A prospective cohort of 84 patients with biopsy-proven HIV+MCD were treated with risk-stratified rituximab-based therapy. Four patients (5%) died of refractory HIV+MCD and 80 achieved clinical remission. The median follow-up for the 80 patients was 6.9 years and their 5-year overall survival was 92% (95% confidence interval [CI], 85 to 99). Eighteen have relapsed (all histologically confirmed), including 5 with concomitant HHV8-associated lymphoma and MCD at relapse. The 5-year relapse-free survival is 82% (95% CI, 72 to 92). No clinical or laboratory findings that were present at MCD diagnosis predicted subsequent relapse, and the median time to first relapse was 30 months (maximum, 10 years). There were no significant differences in clinicopathological features at initial diagnosis and at relapse. All patients were successfully retreated at relapse with rituximab-based therapy. Only 1 patient died of relapsed MCD (at fifth relapse 9.4 years after initial diagnosis). Despite the use of rituximab, the risk of developing HHV8-associated lymphoma was significantly elevated in this cohort, with an incidence of 11.4/1000 person-years. The relatively low relapse rate and high salvage rates at relapse reduce the potential benefit of maintenance therapy; this should only be advocated in the context of a clinical trial.

The cumulative burden of double-stranded DNA virus detection after allogeneic HCT is associated with increased mortality.

Strategies to prevent active infection with certain double-stranded DNA (dsDNA) viruses after allogeneic hematopoietic cell transplantation (HCT) are limited by incomplete understanding of their epidemiology and clinical impact. We retrospectively tested weekly plasma samples from allogeneic HCT recipients at our center from 2007 to 2014. We used quantitative PCR to test for cytomegalovirus, BK polyomavirus, human herpesvirus 6B, HHV-6A, adenovirus, and Epstein-Barr virus between days 0 and 100 post-HCT. We evaluated risk factors for detection of multiple viruses and association of viruses with mortality through day 365 post-HCT with Cox models. Among 404 allogeneic HCT recipients, including 125 cord blood, 125 HLA-mismatched, and 154 HLA-matched HCTs, detection of multiple viruses was common through day 100: 90% had ≥1, 62% had ≥2, 28% had ≥3, and 5% had 4 or 5 viruses. Risk factors for detection of multiple viruses included cord blood or HLA-mismatched HCT, myeloablative conditioning, and acute graft-versus-host disease (P values < .01). Absolute lymphocyte count of <200 cells/mm3 was associated with greater virus exposure on the basis of the maximum cumulative viral load area under the curve (AUC) (P = .054). The maximum cumulative viral load AUC was the best predictor of early (days 0-100) and late (days 101-365) overall mortality (adjusted hazard ratio [aHR] = 1.36, 95% confidence interval [CI] [1.25, 1.49], and aHR = 1.04, 95% CI [1.0, 1.08], respectively) after accounting for immune reconstitution and graft-versus-host disease. In conclusion, detection of multiple dsDNA viruses was frequent after allogeneic HCT and had a dose-dependent association with increased mortality. These data suggest opportunities to improve outcomes with better antiviral strategies.

Interferon Regulatory Factor 1 and Type I Interferon Cooperate To Control Acute Gammaherpesvirus Infection.

Gammaherpesviruses are ubiquitous pathogens that establish lifelong infection in >95% of adults worldwide and are associated with a variety of malignancies. Coevolution of gammaherpesviruses with their hosts has resulted in an intricate relationship between the virus and the host immune system, and perturbation of the virus-host balance results in pathology. Interferon regulatory factor 1 (IRF-1) is a tumor suppressor that is also involved in the regulation of innate and adaptive immune responses. Here, we show that type I interferon (IFN) and IRF-1 cooperate to control acute gammaherpesvirus infection. Specifically, we demonstrate that a combination of IRF-1 and type I IFN signaling ensures host survival during acute gammaherpesvirus infection and supports IFN gamma-mediated suppression of viral replication. Thus, our studies reveal an intriguing cross talk between IRF-1 and type I and II IFNs in the induction of the antiviral state during acute gammaherpesvirus infection. IMPORTANCE: Gammaherpesviruses establish chronic infection in a majority of adults, and this long-term infection is associated with virus-driven development of a range of malignancies. In contrast, a brief period of active gammaherpesvirus replication during acute infection of a naive host is subclinical in most individuals. Here, we discovered that a combination of type I interferon (IFN) signaling and interferon regulatory factor 1 (IRF-1) expression is required to ensure survival of a gammaherpesvirus-infected host past the first 8 days of infection. Specifically, both type I IFN receptor and IRF-1 expression potentiated antiviral effects of type II IFN to restrict gammaherpesvirus replication in vivo, in the lungs, and in vitro, in primary macrophage cultures.

Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study.

BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ). OBJECTIVE: We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. METHODS: We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. RESULTS: Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. CONCLUSION: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.

ROLE OF VIRAL PATHOGENS IN INFANTS WITH SYSTEMIC INFECTION AT THE NEWBORN INTENSIVE CARE UNITS IN GEORGIA.

In Georgia, causative agents among infants with systemic infections are generally not identified and "neonatal sepsis" is usually diagnosed and treated without determining the etiology. The objective of this study was to estimate the role of viral pathogens (Herpesviridae and Enteroviruses) among neonates with generalized infections. A cross-sectional study was performed among neonates younger than <8 weeks admitted to a neonatal intensive care unit (NICU) at the two largest pediatric hospitals in Tbilisi, Georgia. Laboratory tests were performed by consensus and then by type-specific PCR methods. A total of 187 infants were recruited from the NICUs; most participants (74.9%) were of normal birth weight at admission to the NICU and half (51.3%) were younger than 7 days of age. Almost all babies (91.4%) were treated with a broad-spectrum antibiotic despite a lack of microbe identification. While the overall mortality rate of infants with a systemic infection was 21.9 %, neonatal outcomes were more favorable when the infection was due to enteroviruses (2.9% mortality rate) compared to a herpesvirus infection (16.1% mortality rate). Multivariate analyses identified independent predictors associated with neonatal mortality. These included etiology of infection, APGAR score and the type of delivery. Our investigation suggests that viral pathogens play a substantial role in systemic infections among NICU infants. Utilizing molecular-based testing in these cases could improve both the clinical management and outcomes of neonates with generalized infections.

Complete genome sequence and architecture of crucian carp Carassius auratus herpesvirus (CaHV).

Crucian carp Carassius auratus herpesvirus (CaHV) was isolated from diseased crucian carp with acute gill hemorrhages and high mortality. The CaHV genome was sequenced and analyzed. The data showed that it consists of 275,348 bp and contains 150 predicted ORFs. The architecture of the CaHV genome differs from those of four cyprinid herpesviruses (CyHV1, CyHV2, SY-C1, CyHV3), with insertions, deletions and the absence of a terminal direct repeat. Phylogenetic analysis of the DNA polymerase sequences of 17 strains of Herpesvirales members, and the concatenated 12 core ORFs from 10 strains of alloherpesviruses showed that CaHV clustered together with members of the genus Cyprinivirus, family Alloherpesviridae.

THE IMPACT OF ELEPHANT ENDOTHELIOTROPIC HERPESVIRUS ON THE CAPTIVE ASIAN ELEPHANT (ELEPHAS MAXIMUS) POPULATION OF THE UNITED KINGDOM AND IRELAND (1995-2013).

Elephant endotheliotropic herpesvirus (EEHV) is one of the most devastating infections and causes of mortality in captive Asian elephant ( Elephas maximus ) populations. Eight confirmed fatal EEHV cases have occurred since 1995 within the captive Asian elephant population of the United Kingdom and Ireland. This report aims to review the impact of EEHV on the captive Asian elephant population in the United Kingdom and Ireland, document and compare fatal cases, and recommend a framework of monitoring within the United Kingdom and Ireland to increase the success of treatment of EEHV hemorrhagic disease (EEHV HD) in the future. Six zoologic institutions (which include zoos, safari parks, and wildlife parks) that currently house or have previously housed a captive Asian elephant group were included in this report. Medical records and postmortem results were collected from four of these institutions for each confirmed fatal case. EEHV HD was found to be responsible for 29.6% of fatalities in Asian elephants born in captivity in the United Kingdom and Ireland between 1995 and 2013. Following a review of all the cases, it is shown that although clinical signs may be associated with specific EEHV species, the swiftness of disease progression means that most body tissues are impacted 1-6 days following the presentation of visible clinical signs and treatment is less likely to succeed. Therefore, EEHV monitoring should consist of conducting regular polymerase chain reaction analysis of whole blood samples from at-risk, young Asian elephants aged 1-8 yr in order for subclinical viremia to be identified early and treatment to be started before the appearance of visible clinical signs.

Immunosuppressive therapy alleviates murine cytomegalovirus recurrence by reducing TNF-α post cell transplantation with lethal GVHD.

Cytomegalovirus (CMV) reactivation leads to obvious morbidity and mortality in patients after allogeneic hematopoietic cell transplantation (allo-HCT). Current immunosuppressive therapy reduces the frequency of graft-versus-host disease (GVHD), and is generally accepted as a high risk factor for viral recurrence. In the present study, we investigated the influence of cyclosporin A (CsA) and rapamycin (RAPA), two commonly used immunosuppressive agents, on murine cytomegalovirus (MCMV) recurrence by two allo-HCT models: one with mild and one with severe GVHD. In models with mild GVHD and partial immune recovery, transplanted mice with CsA and RAPA showed a higher viral load and impaired CMV-specific immune recovery compared to those with placebo. In contrast, in HCT models with severe GVHD, groups treated with immunosuppressive therapy showed alleviation of viral recurrence as well as GVHD-related symptoms. In addition, no CMV-specific immune reconstitution was found in any group, implying immunosuppressive therapy was not relevant to antiviral response. Furthermore, a significant correlation between MCMV DNA copies and tumor necrosis factor alpha (TNF-α) was found, and recipients with immunosuppressive therapy showed a lower level of TNF-α. Finally, using lenalidomide (an inhibitor of TNF-α), a lower viral load was found in animals with lenalidomide. Having received lenalidomide, recipients showed no statistical difference in viral load between groups with and without immunosuppressive therapy. Taken together, we provide evidence of the dual effect of immunosuppressive therapy on viral reactivation. Importantly, we found that immunosuppressive therapy had the ability to alleviate viral load by reducing TNF-α in a mouse model with severe GVHD.

Herpesvirus Infections and Risk of Frailty and Mortality in Older Women: Women's Health and Aging Studies.

OBJECTIVES: To examine the relationship between herpesvirus infections and mortality and incident frailty risks in community-dwelling older women. DESIGN: Nested prospective cohort study. SETTING: Women's Health and Aging Studies I and II. PARTICIPANTS: Community-dwelling older women aged 70 to 79 (n = 633). MEASUREMENTS: Baseline serum antibody (immunoglobulin G) levels against four herpesviruses (herpes simplex virus types 1 (HSV-1) and 2 (HSV-2), varicella-zoster virus (VZV), 7 Epstein-Barr virus (EBV)), 3-year incident frailty rates, and 5-year mortality. RESULTS: Women seropositive for HSV-1 and HSV-2, but not VZV and EBV, had higher risk of 3-year incident frailty (HSV-1: hazard ratio (HR) = 1.90, 95% confidence interval (CI) = 0.96-3.74; HSV-2: HR = 2.10, 95% CI = 1.05-4.37) and 5-year mortality (HR = 1.73, 95% CI = 0.93-3.20; HR = 1.80, 95% CI = 0.94-3.44, respectively) than seronegative women. Incremental increases in serum HSV-1 and HSV-2 antibody levels were associated with incrementally higher risks of incident frailty and mortality. After adjustment for potential confounders, only higher serum HSV-2 antibody level was independently predictive of higher risk of mortality in older women (for each unit increase in antibody index, HR = 1.47, 95% CI = 1.05-2.07). CONCLUSION: HSV-1 and HSV-2 antibody levels are not independently associated with risk of incident frailty in older women. Only HSV-2 antibody level is independently predictive of 5-year mortality risk, with each incremental increase in the antibody level adding further risk.

Distribution and load of elephant endotheliotropic herpesviruses in tissues from associated fatalities of Asian elephants.

Elephant Endotheliotropic Herpesviruses (EEHVs) are the cause of a highly fatal haemorrhagic disease in elephants primarily affecting young Asian elephants (Elephas maximus) in both captivity and in the wild. The viruses have emerged as a significant threat to Asian elephant conservation, critically affecting overall sustainability of their population. So far insight into the pathogenesis of EEHV infections has been restricted to examination of EEHV-infected tissues. However, little is known about distribution and burden of the viruses within the organs of fatal cases, crucial elements in the understanding of the virus pathogenesis. This study was therefore undertaken to assess the extent of organ and cell involvement in fatal cases of EEHV-1A, 1B and 5 using a quantitative real-time PCR. EEHV-1 and 5 DNA were detectable in all the tissues examined, albeit with substantial differences in the viral DNA load. The highest EEHV-1A DNA load was observed in the liver, followed by the heart, thymus and tongue. EEHV-1B and 5 showed the highest DNA load in the heart, followed by tongue and liver. This study provides new insights into EEHV pathogenicity and has implications in choice of sample type for disease investigation and virus isolation.