Efficacy of live zoster vaccine in preventing zoster and postherpetic neuralgia.

Declining cell-mediated immunity to varicella zoster virus (VZV) in elderly individuals results in virus reactivation manifest by zoster (shingles) and postherpetic neuralgia (PHN). To prevent virus reactivation, a new VZV vaccine (Zostavax; Merck) that boosts cell-mediated immunity to VZV was developed. The 3-year Shingles Prevention Study showed that Zostavax significantly reduced burden of disease because of zoster and PHN. Despite its cost-effectiveness for adults aged 65-75 years, as determined in the United States, Canada and UK, <2% of immunocompetent adults over age 60 years in the United States were immunized in 2007. This was because of a combination of lack of patient awareness of the vaccine, physicians' uncertainty about the duration of protection and different cost-sharing plans for immunization. Nevertheless, zoster vaccine is safe, effective and highly recommended for immunization of immunocompetent individuals over age 60 years with no history of recent zoster.

Review: The neurobiology of varicella zoster virus infection.

Varicella zoster virus (VZV) is a neurotropic herpesvirus that infects nearly all humans. Primary infection usually causes chickenpox (varicella), after which virus becomes latent in cranial nerve ganglia, dorsal root ganglia and autonomic ganglia along the entire neuraxis. Although VZV cannot be isolated from human ganglia, nucleic acid hybridization and, later, polymerase chain reaction proved that VZV is latent in ganglia. Declining VZV-specific host immunity decades after primary infection allows virus to reactivate spontaneously, resulting in shingles (zoster) characterized by pain and rash restricted to one to three dermatomes. Multiple other serious neurological and ocular disorders also result from VZV reactivation. This review summarizes the current state of knowledge of the clinical and pathological complications of neurological and ocular disease produced by VZV reactivation, molecular aspects of VZV latency, VZV virology and VZV-specific immunity, the role of apoptosis in VZV-induced cell death and the development of an animal model provided by simian varicella virus infection of monkeys.

Immunopathogenesis of acute central nervous system disease produced by lymphocytic choriomeningitis virus. II. Adoptive immunization of virus carriers.

Lymphocytic choriomeningitis (LCM) virus carriers were established by intracerebral inoculation of adult BALB/c mice followed by a single dose of cyclophosphamide (CY) (150 mg/kg) 3 days after infection, and by intracerebral injection within 24 hr of birth. These carriers were then adoptively immunized with spleen cells or serum from immune or normal BALB/c donors. Transfer of immune spleen cells into drug-induced carriers consistently resulted in acutely fatal choriomeningitis, histologically strikingly similar to classical LCM. Normal spleen cells or immune serum failed to produce either central nervous system (CNS) pathology or illness with any regularity. In addition, focal necrosis of the cerebellum was seen after adoptive immunization of drug-induced carriers but only when mice received cells at least 3 wk after inoculation, which is probably explained by the gradual spread of infection from membranes to the neural parenchyma during the first month after establishment of the carrier state in adult mice. Immune spleen cells, when transferred to neonatal carriers, led to a decrease in virus titers in blood and brains and to development of antibody without acute CNS disease. It appears that the production of fatal choriomeningitis after LCM infection is determined in part by the distribution of viral antigen, and this is markedly different in neonatal and drug-induced carriers at the time of cell transfer. Another factor of potential importance is the much higher level of circulating viral antigen in the plasma of neonatal than in that of drug-induced LCM carriers. Classical LCM disease can only be transferred by immune lymphoid cells and not by antiserum. Furthermore, little or no complement-fixing (CF) antibody was found in the plasma of mice dying of acute choroiditis. These observations strongly suggest that acute choroiditis is dependent upon the cell-mediated immune response.

Immunopathogenesis of acute central nervous system disease produced by lymphocytic choriomeningitis virus. I. Cyclophosphamide-mediated induction by the virus-carrier state in adult mice.

A single dose of 150 mg/g of cyclophosphamide (CY), given 3 days after intracerebral (i.c.) inoculation of lymphocytic choriomeningitis (LCM) virus, protected over 90% of adult BALB/c mice against acutely fatal choriomeningitis. Surviving mice became persistently infected carriers, with high virus titers in blood and brain. Immunofluorescent examination of the brain showed that in CY-induced carriers infection was initially confined to the choroid plexus, ependyma, and leptomeninges, but over the next 30 days gradually spread to the neural parenchyma, most notably to the molecular layer of the cerebellum. By contrast, LCM virus-carrier mice produced by neonatal virus injection and examined as adults, showed a much less marked infection of choroid plexus and much more widespread infection of parenchyma, with a different distribution among brain nuclei, including heavy infection of the Purkinje cells of the cerebellum.

1/f noise in human cognition.

When a person attempts to produce from memory a given spatial or temporal interval, there is inevitably some error associated with the estimate. The time course of this error was measured in a series of experiments where subjects repeatedly attempted to replicate given target intervals. Sequences of the errors in both spatial and temporal replications were found to fluctuate as 1/f noises. 1/f noise is encountered in a wide variety of physical systems and is theorized to be a characteristic signature of complexity.

Cerebellar hypoplasia in neonatal rats caused by lymphocytic choriomeningitis virus.

Lymphocytic choriomeningitis virus, strain E-350, when inoculated intracerebrally in rats 1 to 7 days old, produces an acute destructive infection of the cerebellar cortex resulting in permanent cerebellar hypoplasia and ataxia. Several other arenoviruses may produce a similar lesion in neonatal rodents.

Chlamydia pneumoniae and multiple sclerosis: no significant association.

The cause of multiple sclerosis (MS) is unknown. Despite indications from epidemiological and identical-twin studies that MS is infectious, no virus or other infectious agent has been tightly linked to disease. The isolation of Chlamydia pneumoniae from the cerebrospinal fluid (CSF) of MS patients and the detection of both Chlamydia-specific DNA and antibody in MS CSF have been reported. Other analyses of brain and CSF have shown no significant difference in C. pneumoniae-specific DNA or antibody between MS and control subjects. Recent work has revealed intrathecal production of C. pneumoniae-specific IgG in only 24% of MS patients compared with 5% of control patients. More importantly, the major CSF oligoclonal bands from MS patients did not react to C. pneumoniae.

Experimental panencephalitis induced in suckling mice by parainfluenza I (6/94) virus. III. Ultrastructural studies.

Intracerebral inoculation of newborn mice with Parainfluenza I (6/94) virus produces a chronic panencephalitis. Electron microscopic studies were carried out over 125 days of the infection. Productive infection of choroidal and ependymal epithelial cells was seen from postinoculation days 2nd to the 8th. Fusion of adjacent choroid and ependymal cells resulted in giant cell formation. Completed virions were seen adsorbed to circulating macrophages and these cells replicated intracytoplasmic nucleocapsids. Neuronal infection was evident on the 3rd postinoculation day, was widespread by the 6th day postinoculation and persisted to the 35th day postinoculation. Nucleocapsid alignment and budding from neuronal plasma membranes was never seen. An initially intense mononuclear cell infiltrate subsided by the 35th day but residual inflammation persisted throughout the study. Late in the course of the infection, vacuolation of the neuropil and a periventricular and deep cerebral spongiform change was seen which could not be directly associated with local viral replication. These ultrastructural findings are correlated with prior light microscopic, virological and immunofluorescent studies of the infection and compared to other experimental models of myxovirus central nervous system infections.

The effect of neonatal thymectomy on Tamiami virus-induced central nervous system disease.

Tamiami virus, a member of the arenavirus group, produces an acute CNS disease in suckling mice manifested primarily by cerebellar ataxia, paralysis, convulsions, and death. Animals that survive are left with an asymptomatic cerebellar heterotopia. Neonatal thymectomy prevents both acute CNS disease and the resultant cerebellar heterotopia despite equivalent titers of virus and concentrations of viral antigen in the brains of both thymectomized and nonthymectomized infected mice. Inflammatory CNS disease and cerebellar germinal cell necrosis do not develop in thymectomized mice examined more than three months after infection. Viremia and complement-fixing antibody occur in both groups of mice with slightly higher antibody titers in nonthymectomized mice. Tamiami virus-induced cerebellar heterotopia appears to be immunologically-mediated, but the immunopathologic cerebellar lesion differs from the frank necrosis of the brain produced by both Tacaribe and LCM virus in newborn mice.

Experimental panencephalitis induced in suckling mice, by parainfluenza type 1 (6/94) virus, II. Virologic studies.

6/94 virus, a parainfluenza type 1 isolate from multiple sclerosis brain tissue, produced a chronic panencephalitis when inoculated intracerebrally into suckling ICR mice. Immunofluorescent staining revealed 6/94 viral antigen in ependyma, meninges, choroid plexus, and perivascular parenchymal sites from day 3 to 128 days after infection. Hemadsorption-neutralizing antibody was first detected between 20-25 days after infection and remained at high titers for 7 months. Using embryonated chicken eggs, virus was recovered from mouse brains for only 8 days, but could be recovered from brains grown in vitro as explants for 37 days after infection. In cell lines established from explanted brain tissue, immunofluorescence was the most sensitive indicator of virus presence, although infectious virus was not produced. Fusion of these mouse brain cells with human (W138) indicator cells was the most effective means of rescuing 6/94 virus.

Human herpesvirus latency.

Herpesviruses are among the most successful human pathogens. In healthy individuals, primary infection is most often inapparent. After primary infection, the virus becomes latent in ganglia or blood mononuclear cells. Three major subfamilies of herpesviruses have been identified based on similar growth characteristics, genomic structure, and tissue predilection. Each herpesvirus has evolved its own unique ecological niche within the host that allows the maintenance of latency over the life of the individual (e.g. the adaptation to specific cell types in establishing latent infection and the mechanisms, including expression of different sets of genes, by which the virus remains latent). Neurotropic alphaherpesviruses become latent in dorsal root ganglia and reactivate to produce epidermal ulceration, either localized (herpes simplex types 1 and 2) or spread over several dermatomes (varicalla-zoster virus). Human cytomegalovirus, the prototype betaherpesvirus, establishes latency in bone marrow-derived myeloid progenitor cells. Reactivation of latent virus is especially serious in transplant recipients and AIDS patients. Lymphotropic gammaherpesviruses (Epstein-Barr virus) reside latent in resting B cells and reactivate to produce various neurologic complications. This review highlights the alphaherpesvirus, specifically herpes simplex virus type 1 and varicella-zoster virus, and describes the characteristics of latent infection.

The expanding spectrum of herpesvirus infections of the nervous system.

Herpesviruses cause various acute, subacute, and chronic disorders of the central (CNS) and peripheral (PNS) nervous systems in adults and children. Both immunocompetent and immunocompromised individuals may be affected. Zoster (shingles), a result of reactivation of varicella zoster virus (VZV), is the most frequent neurologic complication. Other neurological complications include encephalitis produced by type I herpes simplex virus (HSV-1), and less frequently HSV-2, as well as by VZV and cytomegalovirus (CMV). Acute meningitis is seen with VZV and HSV-2, and benign recurrent meningitis with HSV-2. Combinations of meningitis/ encephalitis and myelitis/radiculitis are associated with Epstein Barr Virus (EBV); myelitis with VZV, CMV, EBV, and HSV-2; and ventriculitis/encephalitis with VZV and CMV. Brainstem encephalitis due to HSV and VZV, and polymyeloradiculitis due to CMV are well documented. HHV-6 produces childhood exanthem subitum (roseola) and febrile convulsions. Immunocompetent and immunocompromised hosts manifest different incidences and patterns of herpesvirus infections. For example, stroke due to VZV-mediated large vessel disease (herpes zoster ophthalmicus) occurs predominantly in immunocompetent hosts, while small vessel disease (leukoencephalitis) and ventriculitis develop almost exclusively in immunocompromised patients. EBV-associated primary CNS lymphomas also are restricted to immunosuppressed individuals. Recent large CSF PCR studies have shown that VZV, EBV, and CMV more frequently produce meningitis, encephalitis, or encephalopathy in immunocompetent hosts than was formerly realized. We review herpesvirus infections of the nervous system and illustrate the expanding spectrum of disease by including examples of a 75-year-old male on steroid treatment for chronic lung disease with fatal HSV-2 meningitis and an 81-year-old male with myasthenia gravis, long-term azathioprine use, and an EBV-associated primary CNS lymphoma.

An animal model of varicella virus infection.

Varicella-zoster virus (VZV) causes chickenpox in children; establishes latency in cranial nerve, dorsal root, and autonomic ganglia; and reactivates decades later to produce zoster. VZV produces disease only in humans. Although attempts to produce disease and study VZV latency in experimentally infected animals have resulted in virus in trigeminal or dorsal root ganglia, no clinical signs of infection or reactivation developed. In contrast, simian varicella virus (SVV) produces a naturally occurring exanthematous disease in non-human primates that mimics human varicella. Experimental inoculation of non-human primates causes similar, if not identical, clinical and pathological changes observed in monkeys naturally infected with SVV. Like VZV, SVV becomes latent in ganglia and reactivates, often with entire body rash. SVV and VZV encode antigenically related polypeptides. Both virus genomes have been sequenced and shown to be colinear, sharing up to 75% DNA homology. During latency, an SVV homolog of one of the five VZV genes transcribed in latently infected human ganglia has been detected in monkey ganglia. Preliminary studies in which monkeys were inoculated intratracheally with SVV revealed the presence of viral DNA and RNA in multiple tissues, including blood mononuclear cells, months after experimental infection. These findings differed from the expected restricted localization of the virus DNA to ganglia only and the expected limited viral gene expression, and probably reflect the high virus load delivered intratracheally compared to natural SVV infection in monkeys. Nevertheless, clinical, pathological, and molecular similarities between SVV and VZV indicate that SVV infection in non-human primates has considerable potential as an animal model for human varicella.

Human brain in tissue culture. III. PML-SV40-induced transformation of brain cells and establishment of permanent lines.

Cells from explants and monolayer subcultures of adult human brain obtained from biopsies or autopsies of ten multiple sclerosis (MS) cases, one case each of Jakob-Creutzfeld (JC) and amyotrophic lateral sclerosis (ALS) and three cases with no central nervous system (CNS) involvement were transformed with PML-SV40 virus. Transformation was effected to establish permanent lines of these particular adult brain cells so that sufficient quantities would be available for other research projects. The procedure previously used to transform human fibroblasts (Koprowski et al., '62) was successfully applied to human brain cells. The success of transformation was dependent on the growth condition of the cultures at the time of infection. Events occurring after viral infection and during the pre-transformation and the post-transformation phases are described.

Human brain in tissue culture. IV. Morphological characteristics.

The morphology of cells from normal and diseased brains and PML-SV40 transformed brain cells grown on glass cover slips in cultures is described. Seven types of cells are identifiable, four of which are probably of mesenchymal origin whereas the remaining three are neurologlial. A classification on the basis of the morphologic features is presented.

Human brain in tissue culture. II. Studies of long-term cultures.

This paper describes the techniques used to maintain and reconstitute from storage adult human brain cells in culture. Growth characteristics, cell morphology, lifespan, and karyotypic analysis of cell lines derived from patients with multiple sclerosis (MS), non-MS neurologic diseases, and normal brains are compared.

Human brain in tissue culture. I. Acquisition, initial processing, and establishment of brain cell cultures.

This paper details the in vitro techniques used to establish cells in culture from the brains of 40 patients, most of whom had chronic neurologic disease. The clinical and pathologic features of these patients are given. The success in establihsing cell lines was dependent upon the origin of tissue (biopsy vs. autopsy), the site of removal from the brain, and various environmental and technical manipulations in vitro.

Acute SSPE.

Two patients had acute fulminanting encephalitis and the typical pathological changes of subacute slcerosing panencephalitis (SSPE). It is suggested that SSPE should be considered in the differential diagnosis of acute viral encephalitis.

Hydrocephalus produced by the 6/94 virus; A parainfluenza type 1 isolate from multiple sclerosis brain tissue.

The 6/94 virus, parainfluenza type 1 isolate from multiple sclerosis brain tissue, produced hydrocephalus in newborn Syrian hamsters. All animals developed clinical disease and died within a week. Ependymal cells lining the aqueduct of Sylvius became necrotic and fused, resulting in obstructive hydrocephalus. The 6/94 virus antigen was seen in ependyma and meninges. Paramyxovirus nucleocapsids were seen within cytoplasm of ependymal cells. Virus was recovered from hamster brains for only two days. Infectious virus could be recovered from brains grown in vitro as explants for 21 days. No evidence of rising hemagglutination-inhibiting antibody was noted for up to one month after infection. Intraperitoneal or subcutaneous injection of 6/94 virus did not produce hydrocephalus. HA2 virus and the temperature sensitive mutant of HA2 virus failed to produce hydrocephalus, while Sendai virus caused lesions similar to those of 6/94 virus.

Molecular immunologic strategies to identify antigens and b-cell responses unique to multiple sclerosis.

Identification of the causative agent of multiple sclerosis (MS) has long eluded investigators and has become the "Holy Grail" of researchers in the field. The immune response in cerebrospinal fluid of patients with MS, indicated by an increased IgG level and the presence of specific oligoclonal bands after electrophoresis, strongly parallels that found in various infectious diseases of the central nervous system. To understand the nature of B-lymphocyte activation in MS, 4 laboratories studied the antigen-binding regions of antibodies found in MS brain demyelinative plaques and cerebrospinal fluid. Each analysis revealed (1) limited germline expression, results not expected for a random bystander response; (2) features consistent with a specific antigen-targeted process; and (3) the clonal expansion of populations of B lymphocytes in MS. The screening of libraries expressing protein products derived from chronic MS plaque messenger RNA with antibodies purified from plaques, cerebrospinal fluid, or serum of patients with MS has thus far not revealed the antigenic target(s) of the MS antibody response. Because putative MS antigens could be in low abundance, the screening of large libraries of random peptides expressed on phage surfaces might offer an alternative approach to identify peptide sequences recognized by MS antibodies. New sophisticated molecular immunologic techniques described herein should enhance our ability to identify putative antigen(s) targets in MS.