Studies of the pathogenesis and molecular biology of JC virus infection over the last two decades have significantly changed our understanding of progressive multifocal leukoencephalopathy, which can be described as a subacute viral infection of neuroglial cells that probably follows reactivation of latent infection rather than being the consequence of prolonged JC virus replication in the brain. There is now sufficient evidence to suggest that JC virus latency occurs in kidney and B cells. However, JC virus isolates from brain or kidney differ in the regulatory regions of their viral genomes which are controlled by host cell factors for viral gene expression and replication. DNA sequences of noncoding regions of the viral genome display a certain heterogeneity among isolates from brain and kidney. These data suggest that an archetypal strain of JC virus exists whose sequence is altered during replication in different cell types. The JC virus regulatory region likely plays a significant role in establishing viral latency and must be acted upon for reactivation of the virus. A developing hypothesis is that reactivation takes place from latently infected B lymphocytes that are activated as a result of immune suppression. JC virus enters the brain in the activated B cell. Evidence for this mechanism is the detection of JC virus DNA in peripheral blood lymphocytes and infected B cells in the brains of patients with progressive multifocal leukoencephalopathy. Once virus enters the brain, astrocytes as well as oligodendrocytes support JC virus multiplication. Therefore, JC virus infection of neuroglial cells may impair other neuroglial functions besides the production and maintenance of myelin. Consequently our increased understanding of the pathogenesis of progressive multifocal leukoencephalopathy suggests new ways to intervene in JC virus infection with immunomodulation therapies. Perhaps along with trials of nucleoside analogs or interferon administration, this fatal disease, for which no consensus of antiviral therapy exists, may yield to innovative treatment protocols.

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Progressive multifocal leukoencephalopathy (PML) results from lytic infection of oligodendrocytes by JC virus (JCV). Although JCV has been identified in mononuclear cells in bone marrow and hematogenous dissemination of the virus to the central nervous system has been suspected, JCV has never been clearly demonstrated in the peripheral circulation. Using polymerase chain reaction technology, we examined peripheral lymphocytes of 19 patients with brain biopsy-proven PML for the JCV genome. Two non-PML control groups, consisting of 26 patients seopositive for human immunodeficiency virus type 1 (HIV-1) and 30 immunocompetent patients with Parkinson's disease, were also examined for the presence of the JCV genome in lymphocytes. Cerebrospinal fluid from 10 patients with PML was examined for the presence of the JCV genome as well. The JCV genome was detected in the lymphocytes of 89% (17) of the patients with PML, 38% (10) of the HIV-1-seropositive patients without PML, and none of the patients with Parkinson's disease. Sequencing of the JCV regulatory region from the lymphocytes of three patients revealed the prototype MAD-1 strain of JCV in one patient with PML, a MAD-4 strain in a second patient with PML, and a slightly modified MAD-4 strain in an HIV-1-positive patient without PML. Only 3 of 10 patients with PML who had JCV detected in lymphocytes had the JCV genome in their cerebrospinal fluid. These results demonstrate that the JCV genome can be found in circulating lymphocytes from patients with PML and suggest that lymphocytes are an important vector for hematogenous dissemination of JCV to the central nervous system.(ABSTRACT TRUNCATED AT 250 WORDS)

ease are graphically presented in Fig. 1: (A) JC virions as they assemble in the nucleus of an infected cell in the brain; (B) glial cells, cultured from human brain, which are the targets of virus infection; (C) histopathological plaque lesion of white matter, stained for myelin, that results from that infection; (D) hematoxylin and eosin stain of cells in the lesion identified as macrophages (m) and astrocytes (a); and (E) plaques of demyelinated white matter which represent the neurological impairments characteristic of PML, shown here by magnetic resonance imaging (MRI). The term PML was originally used in 1958 to describe extensive demyelination associated with chronic lymphocytic leukemia (CLL) and Hogdkin's lymphoma (14). However, accounts of similar pathology in patients with dementia were detailed as early as 1930 by Hallervorden (85). A 49 on September 7, 2020 by guest http://cmr.asm.org/ Downloaded from Host Range Studies of JCV in Non-Brain-Derived Cells By using laboratory measurements of JCV growth such as hemagglutination activity, other cells from human and other species were tested for JCV susceptibility. At first, human embryonic kidney, lung, amnion, liver, and intestine were

Owl monkeys were inoculated intracerebrally, subcutaneously, and intravenously with JC, BK, or SV40 virus. Two of four adult owl monkeys inoculated with JC virus, a human polyomavirus, developed brain tumors at 16 and 25 months after inoculation, respectively. A grade 3 to grade 4 astrocytoma (resembling a human glioblastoma multiforme) was found in the left cerebral hemisphere and brainstem of one monkey. The second monkey developed a malignant tumor in the left cerebral hemisphere containing both glial and neuronal cell types. Impression smears prepared from unfixed tissue of this tumor showed cells that contained polyomavirus T antigen. Virion antigens were not detected. Tumor cells cultured in vitro also contained T antigen but were negative for virion antigen. Infectious virus was not isolated from extracts of this tumor.

erpes simplex virus type 2 (HSV-2) infection is responsible for significant neurological morbidity, perhaps more than any other virus. Seroprevalence studies suggest that as many as 45 million people in the United States have been infected with HSV-2, and the estimated incidence of new infection is 1 million annually. Substantial numbers of these persons will manifest neurological symptoms that are generally, although not always, mild and self-limited. Despite a 50% genetic homology between HSV-1 and HSV-2, there are significant differences in the clinical manifestations of these 2 viruses. We herein review the neurological complications of HSV-2 infection.

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Background JC virus (JCV) seropositivity is a risk factor for progressive multifocal leukoencephalopathy (PML) in patients on natalizumab. Accordingly, the JCV serological antibody test is of paramount importance in determining disease risk. Methods We tested the accuracy of the JCV serum antibody test by comparing the results of JCV serology to JC viruria and viremia in 67 patients enrolled in a single-center, retrospective cohort study. Bodily fluids (urine and blood) were assessed for JCV DNA by real time quantitative polymerase chain reaction 6 to 47 months earlier (mean 26.1 months) before JCV antibody testing. In 10 individuals, blood and urine samples were obtained on two separate occasions at 6 month intervals. Results Forty (59.7%) of the 67 patients were JCV seropositive. Of 27 JCV seronegative patients, 10 (37%) had JC viruria. Urine JCV DNA copy numbers were significantly higher in the seropositive group (mean log copy number: 5.93; range 1.85 – 9.21) than the seronegative group (mean log copy number: 2.41; range 1.85 – 5.43) (p=0.0026). Considering all body fluid test results, 50 (74.6%) of the 67 patients were previously infected with JCV. Conclusions The false negative rate of the JCV serology in this study was 37%; therefore, JCV serostatus does not appear to identify all patients infected with JCV. Thus, a negative JCV antibody result should not be conflated with absence of JCV infection. This discordance may be important in understanding JCV biology, risk for PML and PML pathogenesis.