Contributions of neurotropic human herpesviruses herpes simplex virus 1 and human herpesvirus 6 to neurodegenerative disease pathology

Human herpesviruses （HVs） have developed ingenious mechanisms that enable them to traverse the defenses of the central nervous system （CNS）. The ability of HVs to enter a state of latency, a defining char- acteristic of this viral family, allows them to persist in the human host indefinitely. As such, HVs represent the most frequently detected pathogens in the brain. Under constant immune pressure, these infections are largely asymptomatic in healthy hosts. However, many neurotropic HVs have been directly connected with CNS pathology in the context of other stressors and genetic risk factors. In this review, we discuss the potential mechanisms by which neurotropic HVs contribute to neurodegenerative disease （NDD） patholo- gy by highlighting two prominent members of the HV family, herpes simplex virus 1 （HSV-1） and human herpesvirus 6 （HHV-6）. We （i） introduce the infectious pathways and replicative cycles of HSV-1 and HHV-6 and then （ii） review the clinical evidence supporting associations between these viruses and the NDDs Alzheimer＇s disease （AD） and multiple sclerosis （MS）, respectively. We then （iii） highlight and dis- cuss potential mechanisms by which these viruses exert negative effects on neurons and glia. Finally, we （iv） discuss how these viruses could interact with other disease-modifying factors to contribute to the initiation and/or progression of NDDs.

Human herpesvirus 6A induces apoptosis of HSB-2 cellsvia a mitochondrion-related caspase pathway

Apoptosis plays an important role in the pathogenesis of viral infections.In this study,we investigated the cell death processes during productive HHV-6A infection and the underlying mechanisms.Annexin V-PI staining and electron microscopy indicated that HHV-6A is a strong inducer of apoptosis.HHV-6A infection decreased mitochondrial transmembrane potential and led to morphological changes of mitochondria.The cell death was associated with activation of caspase-3 and cleavage of DNA repair enzyme poly （ADP-ribose） polymerase,which is known to be an important substrate for activated caspase-3.Caspase-9 was activated significantly in HHV-6A-infected cells,whereas caspase-8 was not activated obviously.Moreover,HHV-6A infection upregulated Bax and downregulated Bcl-2.This is the first demonstration of mitochondrion-mediated,caspase-dependent apoptosis in HHV-6A-infected cells.

Effectof the Local Strain CN5 of Human Herpesvirus 6 on CD Molecule Expression and PHA-Induced Proliferation of Cord Blood or Peripheral Blood Mononuclear Cells

Cord blood mononuclear cells (CBMC's) and adult peripheral blood mononuclear cells (PBMCs), cultured with RPMI 1640 medium containing 20% fetal calf serum plus 5 mg/L PHA and 10 mg/L IL-Z, were inoculated with CN5 strain of human herpesvirus 6 (HHV 6 ) isolated from a Chinese patient with exanthem subitum and the CN5 infected cell lysates were added to cultures of CBMCs and PBMCs, so as to observe the effects of the local strain CN5 on expression of CD molecule or on proliferation of mononuclear cells by the methods of APAAP staining and MTT assay.The results were as follows: ①Expressions of some CD antigens of CBMCs and PBMCs could change after CN5 strain infection. In both cases, CD3 expresion was down-regulated while CD4 expression was up-regulated. There were no significant differences of CD2, CD8 and CD45RA expressions between the two groups with and without CN5 infection. But the ratio of CD4 to CD8 sigmificantly rose because of the increasing of CD4 positiveity. ②The lysates of CB5-infected CBMCs inhibited the liferation of PBMCs, not of CBMCs, in a protein concentration-dependent pattern. This inhibition was partially neutralized by specific antiserum to CN5, not by antisera to INF-α and TNF-α.

DETECTION OF HUMAN HERPESVIRUS 6(HHV-6) DNA IN SALIVARY GLANDS BY THE POLYMERASE CHAIN REACTION

To assess the presence of HHV-6-Specific DNA in human salivary glands, eighteen specimens of salivary gland tissue were investigated using the polymerase chain reaction. Eight of nine parotid glands, five of seven submandibular glands and one of two sublingual glands were found to have amplification of the HHV-6-specific sequence. The findings suggest that salivary gland tissue is one of the potential sites for HHV-6 persistence following primary infection and that saliva is a vehicle for transmission of the virus.

Human Herpesvirus 6 Infection Complicated by Viral Encephalitis Following Liver Transplantation:A Case Report

Human herpesvirus 6(HHV-6)is a significant pathogen following solid organ transplantation.Here,we report a 64-year-old female with cirrhosis related to nonalcoholic fatty liver disease who underwent orthotopic allogeneic liver transplantation and was ultimately diagnosed with HHV-6 encephalitis through cerebrospinal fluid analysis and MRI.Empirical treatment with daily ganciclovir was initiated according to characteristics indicative of viral encephalitis 3 days before confirmed diagnosis.Subsequent improvement in symptoms was observed,with clearance of HHV-6 from the blood.The complex diagnosis and management of this case accentuate the possibility of serious consequences of HHV-6 infection in postoperative liver transplant patients.Clinicians must maintain a high index of suspicion for HHV-6 reactivation,especially given its association with immunosuppressive drug regimens.Prompt recognition and initiation of antiviral therapy are paramount,particularly when patients present with fever or psychiatric symptoms,as these may indicate HHV-6 encephalitis.

Effects of HHV-6 Infection in Vitro on Cytokines Induction and NK Activity of Peripherial Blood Mononuclear Cells

Three Nanjing local strains (CN5, CN8, CN10) of human herpesvirus 6 (HHV-6] had been isolated and identified by electronmicroscopy, antibody reactions with IFA and specific PCR. The purpose of this paper was to study effects on cytokines synthesis and NK activity of peripheral blood mononuclear cells(PBMC) in vitro post infection of human herpesvirus 6. PBMCs cultural supernatants were collected at different hours post infection. Cytokines such as TNF-α, IFN-α and IL-8 could be detected as early as 24 h post infection, plateaued at 48h, and then decreased gradually. The levels of these cytokines in infected PBMCs supernatants were markedly higher than those in uninfected ones, but the IL-6 level was lower than that of uninfected one. These differences between infected and uninfected groups were all significant(P<0.05). There were no differences in the induction of TNF-α, IFN-α and IL-8 between the local strain CN8 and GS strain (all P>0.05), while the inhibition of IL-6 production induced by GS strain was more prominant than that induced by CN8 (P<0.05). It was also found that NK activity was augmented at 24h post infection, which was more striking in CN8 strain infection group than in GS strain infection group (P<0.05), after then, it was gradually decreased. From these reults, it could be inferred that the increase of cytokines synthesis and augmentation of NK activity were associated with convalescence and pathogenicity of the HHV-6 infection. GS strain, which belongs to groups A, disturbed the function of human immunity more remarkably than the local strain CN8, which belongs to group B.

Isolated ileal perforation due to cytomegalovirus reactivation during management of terbinafine hypersensitivity

We report a case of 71-year-old man who developed a hypersensitivity syndrome associated with terbinafine. He was placed on terbinafine (250 mg/d) for the treatment of tinea pedis due to diabetes mellitus. Following the treatment with terbinafine, he developed druginduced hypersensitivity syndrome (DIHS). Systemic corticosteroid led to transient improvement of his clinical manifestations. Three months after disease onset, he presented with panperitonitis due to ileal perforation, and underwent an emergency operation. The affected ileum was resected and ileostomy was performed in the terminal ileum. Cytomegalovirus (CMV)-specific IgG antibodies were significantly increased, high-titer CMV antigenemia was detected, and pathological examination of the resected ileum confirmed CMV infection. Based onthese observations, we strongly recommend that physicians monitor reactivation of the family of herpesvirus other than herpesvirus 6, to manage DIHS properly.