[Detection rates and high concentration of herpesvirus (Orthoherpesviridae) DNA in autopsy materials from patients with COVID-19 fatal outcome].

INTRODUCTION: SARS-CoV-2 infection causes immune disorders that create conditions for the reactivation of human herpesviruses (HHVs). However, the estimates of the HHVs effect on the course and outcome of COVID-19 are ambiguous. Аim - to study the possible relationship between the HHV reactivation and the adverse outcome of COVID-19. MATERIALS AND METHODS: Postmortem samples from the brain, liver, spleen, lymph nodes and lungs were obtained from 59 patients treated at the Moscow Infectious Diseases Hospital No.1 in 2021-2023. The group 1 comprised 39 patients with fatal COVID-19; group 2 (comparison group) included 20 patients not infected with SARS-CoV-2 who died from various somatic diseases. HHV DNA and SARS-CoV-2 RNA were determined by PCR. RESULTS: HHV DNA was found in autopsy samples from all patients. In group 1, EBV was most often detected in lymph nodes (94%), HHV-6 in liver (68%), CMV in lymph nodes (18%), HSV in brain (16%), VZV in lung and spleen (3% each). The detection rates of HHVs in both groups was similar. Important differences were found in viral load. In patients with COVID-19, the number of samples containing more than 1,000 copies of HHV DNA per 100,000 cells was 52.4%, in the comparison group - 16.6% (p < 0.002). An association has been established between the reactivation of HSV and HHV-6 and the severity of lung damage. Reactivation of EBV correlated with increased levels of liver enzymes. CONCLUSION: Reactivation of HHVs in patients with fatal COVID-19 was associated with severe lung and liver damages, which indicates a link between HHV reactivation and COVID-19 deaths.

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.

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.

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.

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.

Attenuated Salmonella Typhimurium delivery of a novel DNA vaccine induces immune responses and provides protection against duck enteritis virus.

DNA vaccines are widely used to prevent and treat infectious diseases, cancer and autoimmune diseases; however, their relatively low immunogenicity is an obstacle to their use. In this study, we constructed a novel and universal DNA vaccine vector (pSS898) that can be used to build DNA vaccines against duck enteritis virus (DEV) and other viruses that require DNA vaccines to provide protection. This vaccine vector has many advantages, including innate immunogenicity, efficient nuclear trafficking and resistance to attack from nucleases. UL24 and tgB from DEV were chosen as the antigens, and the heat labile enterotoxin B subunit (LTB) from Escherichia coli and the IL-2 gene (DuIL-2) from duck were used as adjuvants for the construction of DNA vaccine plasmids. Ducklings that were orally immunized with S739 (Salmonella Typhimurium Δasd-66 Δcrp-24 Δcya-25) and harboring these DEV DNA vaccines produced strong mucosal and systemic immune responses, and they resisted an otherwise lethal DEV challenge. More importantly, S739 (UL24-LTB) provided 90% protection after a priming-boost immunization. This study shows that our novel and universal DNA vaccine vector can be used efficiently in practical applications and may provide a promising method of orally inoculating ducks with a DEV DNA vaccine delivered by attenuated Salmonella Typhimurium for prevention of DVE.

First detection of Cyprinid Herpesvirus 2 (CyHV-2) in goldfish (Carassius auratus) in France.

Massive mortalities of Carassius auratus (L.) occurred in a farm in France during summer 2014. Fish presented anorexia, loss of scales and large amounts of mucus on the gills. Necrosis of the distal tip of the filament and the lamellae, combined with fusion of the lamellae, was observed, as well as necrosis in the hematopoietic organs and in the digestive tract. The histological examination led to hypothesize the implication of a virus in the mortality. The presence of cyprinid herpesvirus 2 (CyHV-2) in dead fish was demonstrated by amplification and sequencing of portions of the DNA polymerase and helicase genes, both sequences exhibiting 100% identity with CyHV-2 from Japan. In an attempt to find genetic markers of variation, two regions containing tandem repeats in the Japanese genome were amplified from a virus-positive sample from the present outbreak. A first region (mB) was fully identical to the Japanese isolate. However, the second region (mA) exhibited a range of deletions and substitutions compared to CyHV-2 from Japan. This is the first report of CyHV-2 in France in association with mortality of goldfish and the first identification of a molecular marker for its tracing.

Rituximab plus liposomal doxorubicin in HIV-infected patients with KSHV-associated multicentric Castleman disease.

Kaposi sarcoma (KS) herpesvirus-associated multicentric Castleman disease (KSHV-MCD) is a lymphoproliferative disorder, most commonly seen in HIV-infected patients, that has a high mortality if untreated. Concurrent KS is common. Although rituximab has reported activity in KSHV-MCD, its use is often associated with KS progression. Within a natural history study of KSHV-MCD, we prospectively evaluated rituximab 375 mg/m(2) combined with liposomal doxorubicin 20 mg/m(2) (R-Dox) every 3 weeks in 17 patients. Patients received a median of 4 cycles (range 3-9). All received antiretroviral therapy, 11 received consolidation interferon-α, and 6 received consolidation high-dose zidovudine with valganciclovir. Using NCI KSHV-MCD response criteria, major clinical and biochemical responses were attained in 94% and 88% of patients, respectively. With a median 58 months' potential follow-up, 3-year event-free survival was 69% and 3-year overall survival was 81%. During R-Dox therapy, cutaneous KS developed in 1 patient, whereas 5 of 6 patients with it had clinical improvement. R-Dox was associated with significant improvement in anemia and hypoalbuminemia. KSHV viral load, KSHV viral interleukin-6, C-reactive protein, human interleukin-6, and serum immunoglobulin free light chains decreased with therapy. R-Dox is effective in symptomatic KSHV-MCD and may be useful in patients with concurrent KS. This trial was registered at www.clinicaltrials.gov as #NCT00092222.

Factors influencing survivorship of rehabilitating green sea turtles (Chelonia mydas) with fibropapillomatosis.

Marine turtle fibropapillomatosis (FP) is a debilitating, infectious neoplastic disease that has reached epizootic proportions in several tropical and subtropical populations of green turtles (Chelonia mydas). FP represents an important health concern in sea turtle rehabilitation facilities. The objectives of this study were to describe the observed epidemiology, biology, and survival rates of turtles affected by FP (FP+ turtles) in a rehabilitation environment; to evaluate clinical parameters as predictors of survival in affected rehabilitating turtles; and to provide information about case progression scenarios and potential outcomes for FP+ sea turtle patients. A retrospective case series analysis was performed using the medical records of the Georgia Sea Turtle Center (GSTC), Jekyll Island, Georgia, USA, during 2009-2013. Information evaluated included signalment, morphometrics, presenting complaint, time to FP onset, tumor score (0-3), co-morbid conditions, diagnostic test results, therapeutic interventions, and case outcomes. Overall, FP was present in 27/362 (7.5%) of all sea turtles admitted to the GSTC for rehabilitation, either upon admittance or during their rehabilitation. Of these, 25 were green and 2 were Kemp's ridley turtles. Of 10 turtles that had only plaque-like FP lesions, 60% had natural tumor regression, all were released, and they were significantly more likely to survive than those with classic FP (P = 0.02 [0.27-0.75, 95% CI]). Turtles without ocular FP were eight times more likely to survive than those with ocular FP (odds ratio = 8.75, P = 0.032 [1.21-63.43, 95% CI]). Laser-mediated tumor removal surgery is the treatment of choice for FP+ patients at the GSTC; number of surgeries was not significantly related to case outcome.

NOD2/CARD15 single nucleotide polymorphism 13 (3020insC) is associated with risk of sepsis and single nucleotide polymorphism 8 (2104C>T) with herpes viruses reactivation in patients after allogeneic hematopoietic stem cell transplantation.

Three NOD2 polymorphisms (single nucleotide polymorphism [SNP]8 [2104C>T, Arg702Trp], SNP12 [2722G>C, Gly908Arg], and SNP13 [3020insC, Leu1007 fsins C]), identified as disease-associated variants in Crohn's disease, have recently been suggested as gene markers of the outcome of hematopoietic stem cell transplantation (HSCT). In the present multicenter study of 464 donor-recipient pairs, we focused on the effect of NOD2 mutation(s) on the risk of infections and acute graft-versus-host disease (aGVHD). The presence of SNP13 in recipients, donors, or both was more frequently seen in patients having sepsis than in those lacking sepsis (9 of 48 versus 33 of 386, P = .046). The presence of SNP8 (recipient and/or donor positive) was associated with a higher rate of Herpes viruses reactivation (17 of 21 versus 86 of 173, P = .007). In the SNP8-positive group, a trend for a higher rate of bacteremia well controlled by antibiotics was found (9 of 10 versus 47 of 81, P = .106). In contrast, the presence of SNP13 in recipient and/or donor resulted in a poor response to antibiotics (5 of 11 versus 9 of 10, P = .042). A statistically significant association between the presence of NOD2 SNPs and acute grade > II GVHD was found in a subgroup of HSCT patients who received transplants from unrelated donors with a myeloablative conditioning regimen that included antithymocyte globulin (ATG). In this subgroup of patients, donor positivity for any SNPs investigated (7 of 18 versus 17 of 113, P = .036) and, independently, only the presence of SNP8 (4 of 8 versus 20 of 123, P = .055) were associated with severe grade ≥ II aGVHD. In conclusion, SNP8 positivity in donors or recipients makes patients more prone to Herpes viruses reactivation and bacteremia but not to sepsis. Septic complications were associated with SNP13 polymorphism. SNP8 in donors constitutes a risk factor of severe aGVHD, but only if patients received transplants from unrelated donors and received ATG as part of a conditioning regimen.

Myxomavirus-derived serpin prolongs survival and reduces inflammation and hemorrhage in an unrelated lethal mouse viral infection.

Lethal viral infections produce widespread inflammation with vascular leak, clotting, and bleeding (disseminated intravascular coagulation [DIC]), organ failure, and high mortality. Serine proteases in clot-forming (thrombotic) and clot-dissolving (thrombolytic) cascades are activated by an inflammatory cytokine storm and also can induce systemic inflammation with loss of normal serine protease inhibitor (serpin) regulation. Myxomavirus secretes a potent anti-inflammatory serpin, Serp-1, that inhibits clotting factor X (fX) and thrombolytic tissue- and urokinase-type plasminogen activators (tPA and uPA) with anti-inflammatory activity in multiple animal models. Purified serpin significantly improved survival in a murine gammaherpesvirus 68 (MHV68) infection in gamma interferon receptor (IFN-γR) knockout mice, a model for lethal inflammatory vasculitis. Treatment of MHV68-infected mice with neuroserpin, a mammalian serpin that inhibits only tPA and uPA, was ineffective. Serp-1 reduced virus load, lung hemorrhage, and aortic, lung, and colon inflammation in MHV68-infected mice and also reduced virus load. Neuroserpin suppressed a wide range of immune spleen cell responses after MHV68 infection, while Serp-1 selectively increased CD11c(+) splenocytes (macrophage and dendritic cells) and reduced CD11b(+) tissue macrophages. Serp-1 altered gene expression for coagulation and inflammatory responses, whereas neuroserpin did not. Serp-1 treatment was assessed in a second viral infection, mouse-adapted Zaire ebolavirus in wild-type BALB/c mice, with improved survival and reduced tissue necrosis. In summary, treatment with this unique myxomavirus-derived serpin suppresses systemic serine protease and innate immune responses caused by unrelated lethal viral infections (both RNA and DNA viruses), providing a potential new therapeutic approach for treatment of lethal viral sepsis.

Pharmacological inhibition of VIP signaling enhances antiviral immunity and improves survival in murine cytomegalovirus-infected allogeneic bone marrow transplant recipients.

Cytomegalovirus (CMV) infection following allogeneic bone marrow transplant (allo-BMT) is controlled by donor-derived cellular immunity. Vasoactive intestinal peptide (VIP) suppresses Th1 immunity. We hypothesized that blocking VIP-signaling would enhance anti-CMV immunity in murine recipients of allo-BMT. Recipients were transplanted with bone marrow (BM) and T-cells from major histocompatibility complex (MHC)-mismatched VIP-knockout (KO) or wild-type donors, and treated with 7 daily subcutaneous injections of VIPhyb (peptidic VIP-antagonist) or phosphate-buffered saline (PBS). Genetic and pharmacological blockade of VIP-signaling protected allo-BMT recipients from lethal murine CMV (mCMV) infection, improving survival without increasing graft-versus-host disease. Mice treated with VIPhyb or transplanted with VIP-KO allografts had significantly lower viral loads, increased numbers of mCMV-M45-peptide-MHC-tetramer(+) CD8(+) T-cells, with lower PD-1 expression, and enhanced primary and secondary cellular immune responses after mCMV infection than did PBS-treated mice. These results demonstrate that administration of a VIP antagonist after allo-BMT is a promising safely therapeutic approach to enhance antiviral cellular immunity.

Massive mortality of Prussian carp Carassius gibelio in the upper Elbe basin associated with herpesviral hematopoietic necrosis (CyHV-2).

From 22 May to 10 June 2011 massive mortality of Prussian carp Carassius gibelio was observed in alluvial Lake Rehacˇka close to the Elbe River in the Czech Republic. More than 1400 kg of dead fish were collected and no other fish species were affected. Further molecular and cytogenetic investigation of fish (n = 232) revealed that the Rˇehacˇka population of Prussian carp consisted exclusively of gynogenetic triploid females. The causative agent was identified by means of molecular and electron microscopy as a herpesviral hematopoietic necrosis virus (Cyprinid herpesvirus 2, CyHV-2). This is the first report of CyHV-2 from the Czech Republic and the second finding worldwide of CyHV-2 causing mass mortality of C. gibelio. Some other localities in the upper Elbe River basin where C. gibelio was affected are also noted. We assume that the massive wave of deaths of all female gynogenetic Prussian carp can be attributed to limited genetic variation and the favourable conditions for development of viral disease.

Association between transfusion with human herpesvirus 8 antibody-positive blood and subsequent mortality.

BACKGROUND: Human herpesvirus 8 (HHV-8) is endemic in Uganda and transmissible by blood. We evaluated mortality following transfusion of HHV-8 antibody-positive blood. METHODS: In a hospital-based, observational, prospective cohort study with a 6-month follow-up, we examined the effect of HHV-8 antibody-positive blood on transfusion recipients surviving at least 7 days. RESULTS: Of 1092 recipients, 471 (43.1%) were transfused with HHV-8 antibody-positive blood. Median age was 1.8 years (range, 0.1-78); 111 (10.2%) died during follow-up. After adjusting for confounders (increasing age, human immunodeficiency virus infection, illness other than malaria, receipt of multiple transfusions), recipients of HHV-8 antibody-positive blood stored ≤4 days ("short-stored") were more likely to die than recipients of HHV-8 antibody-negative blood (adjusted hazards ratio [AHR], 1.92; 95% confidence interval [CI], 1.21-3.05; P = .01). The AHR of the effect of each additional short-stored HHV-8 antibody-positive transfusion was 1.79 (95% CI, 1.33-2.41; P = .001). CONCLUSIONS: Transfusion with short-stored HHV-8 antibody-positive blood was associated with an increased risk of death. Further research is warranted to determine if a causal pathway exists and to verify the observed association between acute HHV-8 infection and premature mortality.

A novel herpesvirus in 3 species of pheasants: mountain peacock pheasant (Polyplectron inopinatum), Malayan peacock pheasant (Polyplectron malacense), and Congo peafowl (Afropavo congensis).

The mountain peacock pheasant (Polyplectron inopinatum), the Malayan peacock pheasant (Polyplectron malacense), and the Congo peafowl (Afropavo congensis) are all listed as vulnerable to extinction under the International Union for Conservation of Nature Red List of Threatened Species. Here the authors report fatal infection with a novel herpesvirus in all 3 species of birds. DNA was extracted from the livers of birds with hepatocellular necrosis and intranuclear eosinophilic inclusions consistent with herpesvirus infection. Based on degenerate herpesvirus primers and polymerase chain reaction, 220- and 519-base pair products of the herpes DNA polymerase and DNA terminase genes, respectively, were amplified. Sequence analysis revealed that all birds were likely infected with the same virus. At the nucleotide level, the pheasant herpesvirus had 92% identity with gallid herpesvirus 3 and 77.7% identity with gallid herpesvirus 2. At the amino acid level, the herpes virus had 93.8% identity with gallid herpesvirus 3 and 89.4% identity with gallid herpesvirus 2. These findings indicate that the closest relative to this novel herpesvirus is gallid herpesvirus 3, a nonpathogenic virus used widely in a vaccine against Marek's disease. In situ hybridization using probes specific to the peacock pheasant herpesvirus DNA polymerase revealed strong intranuclear staining in the necrotic liver lesions of an infected Malayan peacock pheasant but no staining in normal liver from an uninfected bird. The phasianid herpesvirus reported here is a novel member of the genus Mardivirus of the subfamily Alphaherpesvirinae and is distinct from other galliform herpesviruses.