Berberine in Human Oncogenic Herpesvirus Infections and Their Linked Cancers

Human herpesviruses are known to induce a broad spectrum of diseases, ranging from common cold sores to cancer, and infections with some types of these viruses, known as human oncogenic herpesviruses (HOHVs), can cause cancer. Challenges with viral latency, recurrent infections, and drug resistance have generated the need for finding new drugs with the ability to overcome these barriers. Berberine (BBR), a naturally occurring alkaloid, is known for its multiple biological activities, including antiviral and anticancer effects. This paper comprehensively compiles all studies that have featured anti-HOHV properties of BBR along with promising preventive effects against the associated cancers. The mechanisms and pathways induced by BBR via targeting the herpesvirus life cycle and the pathogenesis of the linked malignancies are reviewed. Approaches to enhance the therapeutic efficacy of BBR and its use in clinical practice as an anti-herpesvirus drug are also discussed.     

Very late‐onset cytomegalovirus disease with ganciclovir resistance >15 years following renal transplantation

Cytomegalovirus (CMV) infection is a significant cause of morbidity and mortality after solid organ transplantation. There has been a significant shift in disease epidemiology with the introduction of antiviral prophylaxis, with CMV disease occurring later and clinical presentations more atypical. We describe two cases of very late‐onset CMV disease where first disease occurred 15 and 18 years post–renal transplantation, with both cases complicated by antiviral drug resistance. We subsequently review the published cases and literature of very late‐onset CMV disease (onset > 10 years post–solid organ transplantation) as an increasingly recognized phenomenon which is emerging as an important aspect in improving long‐term patient outcomes in the current era of renal transplantation.     

Reactivations of Latent Viral Infections Are Associated with an Increased Thr389 p70S6k Phosphorylation in Peripheral Lymphocytes of Renal Transplant Recipients

Reactivations of BK polyoma virus (BKPyV) and human cytomegalovirus (HCMV) frequently cause life- and graft-threatening complications after renal transplantation. Both viruses are dependent on the mTOR pathway for replication. In this study we investigated the association of viral replication with mTOR activity in peripheral lymphocytes of renal transplant recipients. A flow-cytometry based assay for the measurement of Thr389 p70S6k phosphorylation, a surrogate marker of the mTOR pathway was established. Forty-eight adult renal transplant recipients were recruited to measure p70S6k activity in their peripheral blood mononuclear cells. This data set in conjunction with information concerning previous replication of BKPyV and HCMV was examined for correlations. Episodes of BKPyV replication were significantly associated with increased p70S6k phosphorylation in CD4⁺ T lymphocytes (p = 0.0002) and CD19⁺ B lymphocytes (p = 0.0073). HCMV infection of patients with a high-risk HCMV constellation of donor and recipient (D+/R−) was associated with increased p70S6k phosphorylation in CD19⁺ B lymphocytes (p = 0.0325). These associations were found to be independent of the trough levels of the immunosuppressive drugs. Conclusion: P70S6k phosphorylation in peripheral lymphocytes is associated with BKPyV reactivations and to a lesser extent with HCMV infections in renal transplant recipients.     

Human cytomegalovirus-specific immunity following haemopoietic stem cell transplantation

The herpesvirus Human Cytomegalovirus (HCMV) is an important opportunistic infection in recipients of allogeneic haemopoietic stem cell transplants, in whom HCMV-specific CD8+ and CD4+ T-cell responses are impaired. The nature of the HCMV-specific T-cell response in healthy virus carriers has been characterised in detail. High frequencies of circulating CD8+ T-cells that recognise defined viral peptides are maintained for years, and include individual CD8+ clones that have undergone extensive clonal expansion and phenotypic diversification in vivo. Following stem cell transplantation, the kinetics of HCMV-specific CD8+ T-cell reconstitution in the recipient are related to the presence or absence of antigen-experienced CD8+ T-cells transferred via the allograft, and to the presence of the virus in the recipient. We discuss recent progress in our understanding of HCMV-specific immunity in healthy virus carriers and in recipients after alloSCT.     

人巨细胞病毒先天性潜伏感染再激活致老年小鼠肝脏的损伤

目的:建立HCMV先天性潜伏感染再激活致肝脏损伤的BALB/c老年小鼠模型,初步探讨HCMV潜伏再激活感染的致病机制.方法:建立HCMV先天性感染小鼠的模型,将子代小鼠饲养于SPF级屏障系统中18mo后,从子代小鼠中分别取病毒感染组18只、细胞对照组9只,随机将病毒感染组中半数进行环磷酰胺激活,建立HCMV潜伏再激活感染鼠模型,按照实验设计分别处死细胞对照组、病毒潜伏组和病毒潜伏再激活组小鼠,无菌取出小鼠肝组织,进行病毒分离、PCR、RT-PCR及HE染色.结果:潜伏再激活组小鼠的肝组织匀浆上液中分离出HCMV,在病毒分离出现细胞病变效应(CPE)的细胞培养液中检测HCMVDNA;HE染色证实肝组织有炎性改变,肝细胞肿大,核内有嗜酸性包涵体等;PCR检测到HCMVDNA,RT-PCR检测到组织中HCMVmRNA.病毒潜伏组仅PCR检测到HCMVDNA,其它与细胞对照组一样均是阴性.结论:HCMV先天性潜伏感染再激活导致肝脏病理损伤.     

巨细胞病毒感染与动脉粥样硬化关系的研究

近年,动脉粥样硬化(Atherosclerosis,As)发生的病毒病因学研究日益受到人们的关注.本研究通过应用ELISA、PCR及原位杂交等技术对45例As病人及22例正常者血清及血管组织配对标本检测了HCMV—sIgG、sIgM及HCMV IE、L基因片段,以及其在血管组织中的分布.结果显示:As组中HCMV—sIgG抗体水平显著高于对照组,sIgM仅见于As组.HCMV IE及L基因的阳性率也显著高于对照,并且发现HCMV DNA多见于内膜下肌层及中膜平滑肌的细胞核,强烈提示HCMV感染与As的发生密切相关.同时,本文还就HCMV—sIgG及sIgM与HCMV基因检出的关系及意义作了探讨,为As的临床早期诊断、早期预防及针对性治疗奠定了基础.     

Cytomegalovirus infection and disease after liver transplantation

Cytomegalovirus is the single most important pathogen in clinical transplantation. Although much progress has been made in our understanding of the molecular biology and epidemiology of CMV infection and in our ability to diagnosis and treat CMV disease, it remains a major cause of morbidity but is no longer a major cause of mortality after liver transplantation. Risk factors for CMV disease after liver transplantation include donor and recipient serologic status, the use of antilymphocyte therapy, and retransplantation. CMV disease occurs early after transplantation, and the most frequent site of disease is the hepatic allograft. We have treated 79 patients with intravenous ganciclovir, with ultimate control of disease achieved in 69 patients (87.3%). Preliminary results using intravenous immunoglobulin and oral acyclovir for CMV prophylaxis in high-risk patients have been encouraging. In addition to producing clinical syndromes, CMV may have direct immunologic effects and is a marker of the net state of immunosuppression.     

Clinical and histological features of cytomegalovirus hepatitis in previously healthy adults

Abstract: It is well known that cytomegalovirus infection is often accompanied by hepatitis, but there have been few comparative studies with respect to clinical features of cytomegalovirus-associated hepatitis and other acute viral hepatitides. In the present study, clinical and pathological features of 11 acute sporadic cytomegalovirus hepatitis infections in previously healthy adults were compared with those of 45 acute sporadic viral hepatitis, including type A, type B and type C. As a result, the characteristics of cytomegalovirus hepatitis were a long-lasting fever, splenomegaly, atypical lymphocytosis, a mild transaminasemia, a low ratio of alanine aminotransferase level to lactate dehydrogenase level, and mild hepatic histopathological changes.