Focal neurological deficits and West Nile virus infection.

Our experience with West Nile virus infection revealed that 54% of 28 patients had a focal neurological deficit at presentation. A meningitis or encephalitis syndrome was absent in 47% of patients with focal deficits. Details of the variety of deficits, the time to development of deficits, and the associated radiological and laboratory findings are also discussed in the present report.

Oncogenic potential of human neurotropic papovavirus, JCV, in CNS.

The human polyomavirus, JCV, is the causative agent of Progressive Multifocal Leukoencephalopathy (PML), a fatal human demyelinating disease. PML results from the cytolytic destruction of oligodendrocytes, the myelin-producing cells of the nervous system. JCV has also been shown to be tumorigenic in several animal models. Transgenic mice expressing the JCV early protein, T-antigen, develop poorly differentiated neural crest origin tumours. Intracerebral inoculation of JCV into newborn hamsters induces medulloblastomas, astrocytomas, and primitive neuroectodermal tumours. Further, inoculation of the virus into the brains of non-human primates, owl and squirrel monkeys, results in astrocytomas and glioblastoma multiforme. Several case reports have associated JCV with human CNS tumours in patients with concomitant PML, and one such report has detected JCV in a glial tumour in the absence of PML. The induction of neural origin tumours by JCV has been studied in transgenic mice harbouring the early genome of the virus. Alterations in the level and function of tumour suppressor proteins p53 and Rb, as well as associated cell cycle regulators, have been detected in tumour tissue from JCV T-antigen transgenic mice. Possible mechanisms by which JCV may exert its oncogenic potential by alteration of cellular growth control pathways in both humans and experimental animals are discussed.

Review: JC virus infection of lymphocytes--revisited.

JC virus (JCV), the causative agent of the fatal human demyelinating disease progressive multifocal leukoencephalopathy (PML), is an opportunistic papovavirus that infects and destroys oligodendrocytes, the myelin-producing cells of the central nervous system. Since its isolation from the brain of a PML patient, JCV has long been classed as a neurotropic virus. Many studies, however, have demonstrated that JCV can infect various other cell types, including immune system cells. Moreover, several recent studies have focused specifically on lymphocytes as a target of JCV. This review chronicles the association of JCV with lymphocytes, including cell type localization, molecular regulation, and viral sequences, and discusses clinical implications of these findings.

Human T-cell lymphotropic virus type II-associated myelopathy: clinical and immunologic profiles.

Human T-cell lymphotropic virus type II (HTLV-II) is endemic in several ethnic tribes and among intravenous drug users in metropolitan areas. Despite the presence of HTLV-II in these various populations, the association of HTLV-II with disease is sparse and mainly limited to isolated case reports. This study is an extension of an earlier description of an HTLV-II-infected patient with neurologic disease and presents the clinical and immunologic findings of 4 patients with HTLV-II seropositivity and spastic paraparesis. The patients are of African-American origin with 3 of the patients being of Amerindian descent. All of the patients are seronegative for the human immunodeficiency virus (HIV). The patients progressed to a nonambulatory state in less than 5 years. Magnetic resonance imaging studies obtained from 3 of the patients demonstrated white matter disease in the cerebrum and spinal cord. The cerebrospinal fluid and serum contained antibodies to HTLV-II. The presence of proviral HTLV-II was confirmed by polymerase chain reaction analysis of peripheral blood lymphocytes (PBLs). A spinal cord biopsy from 1 patient demonstrated HTLV RNA within a lesion. Immunologic studies on 2 patients demonstrated that spontaneous lymphoproliferation of PBLs was present but decreased relative to HTLV-I-infected patients. The clinical and immunologic findings from these HTLV-II-infected patient resemble those found in HTLV-I-associated myelopathy/tropical spastic paraparesis.

Zoster myelitis: improvement with antiviral therapy in two cases.

This report describes two patients with acquired immunodeficiency syndrome (AIDS) and herpes zoster myelopathy. Patient one had a T-8 myelitis that preceded the onset of T-8-distribution zoster and was followed by cervical myelopathy. Antibody to varicella zoster virus (VZV) was present in the CSF. He never received steroids or other immunosuppressive drugs, and his condition improved dramatically after treatment with intravenous acyclovir. The second patient had a rapidly progressive myelitis with paralysis of both legs. Detection of VZV DNA and antibody to VZV in his CSF led to successful treatment with famciclovir despite discontinuation of dexamethasone and earlier treatment failure with acyclovir. These cases support the idea that VZV myelopathy in the immunosuppressed host is caused by virus invasion. CSF analysis for antiviral antibody and for VZV DNA by polymerase chain reaction are helpful in establishing the diagnosis. Aggressive antiviral therapy is advised.

Detection of JC virus DNA in peripheral lymphocytes from patients with and without progressive multifocal leukoencephalopathy.

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)

Relapsing and remitting human immunodeficiency virus-associated leukoencephalomyelopathy.

We describe a 33-year-old homosexual man with a steroid-responsive, remitting and relapsing leukoencephalopathy associated with recent human immunodeficiency virus type 1 (HIV-1) seroconversion. Biopsy of a parieto-occipital lesion revealed demyelination and astrogliosis with focal necrosis. Detailed investigations demonstrated no pathogens in the brain other than HIV-1. This patient illustrates that a neurological disorder clinically indistinguishable from multiple sclerosis may be the presenting manifestation of HIV-1 infection and may occur in the absence of clinically significant immunosuppression.

Pathogenesis and molecular biology of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain.

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.

Glial cells of the human developing brain and B cells of the immune system share a common DNA binding factor for recognition of the regulatory sequences of the human polyomavirus, JCV.

Cells of the nervous system and the immune system perform highly specialized functions which reflect the tissue-specific regulation of their genes. However there are some functions between these two cell systems such as antigen presentation, cytokine release, and expression of MHC molecules which suggest a common mechanism for regulation of certain genes. We present data that extend this observation to include the recognition of specific neurotropic viral DNA sequences by glial cells and B cells. The experiments here provide evidence that both human glial cells and B cells possess nuclear DNA binding proteins that interact with nucleotide sequences on the regulatory region of the JC viral genome. These DNA binding proteins are present in human lymphoma B cell lines and fetal glial cultures. The fetal glial cultures are characterized as astrocytes by unique cDNA expression and the presence of GFAP. Data are also presented that demonstrate the presence of JCV infected B cells in brain tissue derived from progressive multifocal leucoencephalopathy, the demyelinating disease caused by JCV infection. The possibility that the glial and B cell protein factor(s) responsible for recognition of the JCV genome belong to a family of proteins similar to known transcriptional control elements such as the Octamer binding proteins or Nuclear Factor-1 is discussed.

A rapid method for in situ hybridization for viral DNA in brain biopsies from patients with AIDS.

Brain biopsy is often necessary in the diagnosis of neurological complications found in AIDS patients. We describe here a rapid method of tissue preparation and in situ DNA hybridization for detecting JC virus DNA in frozen brain biopsy sections which allows the diagnosis of progressive multifocal leukoencephalopathy to be established on the day of surgery. Once the diagnosis is established, therapeutic and management decisions can be made more easily. The commercial availability of biotinylated probes for several of the DNA viruses most frequently encountered in brain infections of AIDS patients will provide wide application of these techniques to patient management.

Experimental congenital disease with simian cytomegalovirus in rhesus monkeys.

Cytomegalovirus (CMV) infections occur worldwide and are responsible for severe damage to the child in from one to five newborns per 20,000 births. Animal models of congenital CMV infection resulting in disease have been developed in mice and guinea pigs. We report here the development of ventricular dilatation and leptomeningitis in rhesus monkeys, Macaca mulatta, following intrauterine infection with rhesus cytomegalovirus (RCMV). Central nervous system (CNS) lesions were associated with low cytomegalovirus fluorescent antibody titers in affected fetuses. In several infected animals, RCMV was isolated at necropsy from neural and nonneural tissues taken shortly after birth. This model allows investigators to study the pathogenesis and prevention of CNS changes following RCMV infection.

Echovirus meningomyeloencephalitis with administration of intrathecal immunoglobulin.

Echovirus meningomyeloencephalitis was treated with cerebral intraventricular immunoglobulin. This case includes a complete examination of the central nervous system (CNS) supported by viral culture studies, immunoperoxidase staining and electron microscopy. Neuronal loss was most severe in the cerebellum and spinal cord. This may lead to the ataxia and a poliomyelitis-like syndrome often seen in cases of echovirus meningomyeloencephalitis. Focal encephalitic lesions, antigen-antibody reactions and live virus were found at numerous levels of the CNS in spite of intrathecal and intravenous immunoglobulin therapy. This mode of therapy and the electron microscopic features noted in echovirus infections are discussed.

Retrovirus-like particles in salivary glands, prostate and testes of AIDS patients.

AIDS associated retrovirus-like particles were identified in the salivary gland, prostate and/or testicle of two AIDS patients. These findings further suggest that saliva and semen may transmit the infection to susceptible individuals.

PIP: This article presents electronmicroscopy evidence of retrovirus-like particles with bar shaped cores in salivary and prostate glands as well as testicles of 2 acquired immunodeficiency syndrome (AIDS) patients. The 1st case, a 38-year old black male homosexual, presented in 1982 with diarrhea, malabsorption, and weight loss. In the following 1 1/2 years, he experienced recurrent Candida esophagitis, cutaneous and pulmonary Kaposi's sarcoma, Pneumocystis carinii pneumonia, and cytomegalovirus. Autopsy in 1984 revealed residual Kaposi's sarcoma, disseminated cytomegalovirus, and M avium-intracellulare. The 2nd case, a 31-year old white male homosexual, presented in 1984 with Pneumocystis carinii penumonia and subsequently developed persistent fever, hepatomegaly, headaches, blurred vision, progressive liver function deterioration, and disseminated histoplasmosis infection. Autopsy in 1984 revealed an overwhelming disseminated histoplasmosis infection. Tissues taken at postmortem were examined by electron microscopy. Particles that conformed with the morphologic characteristics of AIDS retrovirus (a size of about 140 nm, a round shape with a double membrane, and an elongated core) were detected in the prostate gland of patient 2 and in the salivary glands and testes of both patients. This finding suggests that saliva and semen may be body fluids by which transmission of the AIDS virus occurs.

Transmission of simian acquired immunodeficiency syndrome (SAIDS) with type D retrovirus isolated from saliva or urine.

Saliva and urine specimens from rhesus monkeys with SAIDS were found to contain a type D retrovirus related to Mason-Pfizer monkey virus (MPMV) which has been linked etiologically to SAIDS. Virus isolates from saliva and urine were shown to have the characteristics of the SAIDS agent by their reverse transcriptase divalent cation preference for synthetic template-primers, production of characteristic cytopathology in Raji cells and antigenic relatedness to MPMV as determined by enzyme-linked immunosorbent assay (ELISA) and competition radioimmunoassay (RIA). Electron micrographs of parotid tissue from an animal with SAIDS also showed budding particles with type D retrovirus morphology. A tissue culture grown virus isolate from urine of an animal with SAIDS, produced SAIDS when inoculated into two normal juvenile rhesus monkeys. Since saliva and urine of monkeys with SAIDS contain infectious SAIDS virus, they are likely sources of virus by which the disease is naturally transmitted. Thus, care should be taken to avoid contact of normal and infected animals.

Transmission of simian acquired immunodeficiency syndrome (SAIDS) with blood or filtered plasma.

Simian acquired immunodeficiency syndrome (SAIDS), a disease clinically and pathologically similar to acquired immunodeficiency syndrome in humans, was transmitted from diseased rhesus monkeys (Macaca mulatta) to normal monkeys by inoculation with heparinized whole blood or plasma that had been passed through filters of 0.45 micrometer pore size. This suggests that the causative agent is small and most probably a virus. No viruses, however, were isolated by standard cell culture techniques from the blood or filtered plasma which caused SAIDS. Both cellular and humoral immunity were markedly depressed in animals with advanced SAIDS.

Experimental transmission of simian acquired immunodeficiency syndrome (SAIDS) and Kaposi-like skin lesions.

A disease that is similar to human AIDS may occur in monkeys. Simian AIDS (SAIDS) was experimentally transmitted from 2 rhesus monkeys dying of the disease to 4 cytomegalovirus (CMV) antibody-negative rhesus monkeys. The inocula consisted of the supernatant fluid from 10% homogenates of various tissues with or without buffy-coat cells from blood. Lymphadenopathy, splenomegaly, neutropenia, polymyositis, and other signs of the disease appeared in recipients within a few weeks after inoculation. Two animals developed Kaposi-like "patch" and "plaque" skin lesions and one died of sepsis and profound lymphoid depletion. A second animal also died with lymphoid depletion. All animals became infected with CMV but antibody levels were low in two animals, appeared and then disappeared in one, and never developed in the second monkey which died.