Phenotype-genotype analysis of dystrophinopathy caused by duplication mutation in Dystrophin gene in an African patient.

BACKGROUND: The dystrophinopathies, duchenne muscular dystrophy (DMD) and Becker muscular dystrophy are common X-linked genetic myopathies resulting from mutations in the dystrophin gene. Duplication is an uncommon mechanism of mutation occurring in about 5% of DMD cases. The global prevalence of DMD is reported as 1/18,000 males. There is little clinical or epidemiological data on African patients. OBJECTIVE: To present the genotype-phenotype analysis of dystrophinopathy with an exon 8 through 9 duplication mutation in a patient of African/Ghanaian descent and his asymptomatic mother. METHODS: Investigations including a biopsy of the vastus lateralis muscle and genetic testing of the patient and his mother. RESULTS: Genetic testing demonstrated a duplication of exons 8 through 9 of the dystrophin gene in both the patient and his mother. The muscle biopsy of the patient showed partial expression of the dystrophin protein. In the absence of a family history of dystrophinopathy, we hypothesize that this is a sporadic mutation occurring in the grand maternal lineage. CONCLUSION: This case extends the world wide epidemiology of this disease to include the African/Ghanaian population and confirms the vulnerability of the dystrophin gene to recurrent spontaneous mutations at the exon 8 and 9 site.

Oligoclonal T cells are infiltrating the brains of children with AIDS: sequence analysis reveals high proportions of identical beta-chain T-cell receptor transcripts.

We have recently described the presence of perivascular CD3+ CD45RO+ T cells infiltrating the brains of children with AIDS. To determine whether these infiltrates contain oligoclonal populations of T cells, we amplified by PCR beta-chain T-cell receptor (TCR) transcripts from autopsy brains of four paediatric patients with AIDS. The amplified transcripts were cloned and sequenced. Sequence analysis of the beta-chain TCR transcripts from all four patients revealed multiple identical copies of TCR beta-chain transcripts, suggesting the presence of oligoclonal populations of T-cells. These TCR transcripts were novel. The presence of oligoclonal populations of T cells in the brains of these four paediatric patients with AIDS suggests that these T cells have undergone antigen-driven proliferation and clonal expansion very likely in situ, in the brains of these AIDS patients, in response to viral or self-antigens. Although the specificity of the clonally expanded beta-chain TCR transcripts remains to be elucidated, none of the beta-chain TCR transcripts identified in this study were identical to those specific for HIV-1 antigens that are currently reported in the GENBANK/EMBL databases. Certain common CDR3 motifs were observed in brain-infiltrating T cells within and between certain patients. Large proportions (24 of 61; 39%) of beta-chain TCR clones from one patient (NP95-73) and 2 of 27 (7%) of another patient (NP95-184-O) exhibited substantial CDR3 homology to myelin basic protein (MBP)-specific TCR derived from normal donors or TCR expressed in the brain of patients with multiple sclerosis (MS) or with viral encephalitis. These two patients (NP95-73 and NP95-184-O) also shared HLA class II with the normal donors and the MS patients who expressed these homologous TCR. Pathologic examination at autopsy of the brains revealed the presence of myelin pallor only in patient NP95-73. T-cell clones identified in the brain of patients NP95-73 and NP95-184-O may recognize MBP or another CNS self antigen and this recognition may be restricted by either DRB1*15 or DQB1*0602 specificities.

Detection of HIV-1 DNA in microglia/macrophages, astrocytes and neurons isolated from brain tissue with HIV-1 encephalitis by laser capture microdissection.

In HIV-1 encephalitis, HIV-1 replicates predominantly in macrophages and microglia. Astrocytes also carry HIV-1, but the infection of oligodendrocytes and neurons is debated. In this study we examined the presence of HIV-1 DNA in different brain cell types in 6 paraffin embedded, archival post-mortem pediatric and adult brain tissues with HIV-1 encephalitis by Laser Capture Microdissection (LCM). Sections from frontal cortex and basal ganglia were stained by immunohistochemistry for CD68 (microglia), GFAP (astrocytes), MAP2 (neurons), and p24 (HIV-1 positive cells) and different cell types were microdissected by LCM. Individual cells or pools of same type of cells were lysed, the cell lysates were subjected to PCR using HIV-1 gag SK38/SK39 primers, and presence of HIV-1 DNA was confirmed by Southern blotting. HIV-1 gag DNA was consistently detected by this procedure in the frontal cortex and basal ganglia in 1 to 20 p24 HIV-1 capsid positive cells, and in pools of 50 to 100 microglia/macrophage cells, 100 to 200 astrocytes, and 100 to 200 neurons in HIV-1 positive cases but not in HIV-1 negative controls. These findings suggest that in addition to microglia, the infection of astrocytes and neurons by HIV-1 may contribute to the development of HIV-1 disease in the brain.

Immunopathology of secondary-progressive multiple sclerosis.

Twenty-three plaques obtained at early autopsy from 2 patients with secondary-progressive multiple sclerosis were examined immunohistochemically for microglia/macrophages, and for immunoglobulins and components of activated complement. Most of the lesions examined in both cases exhibited evidence of low-grade active demyelination of an unusual type (frustrated phagocytosis) in periplaque white matter. This included linear groups of microglia engaging short segments of disrupted myelin that were associated with deposits of C3d, an opsonin formed during complement activation. Similar microglia/C3d/myelin profiles were not observed in newly forming lesions in cases of acute multiple sclerosis or other central white matter diseases. As C3d coupling is known to increase the immunogenicity of potential antigens enormously, present findings point to disrupted myelin close to plaques as a possible source of the putative multiple sclerosis antigen. Ongoing myelin destruction found in a high proportion of old, established plaques was surprising. It suggests that slowly expanding lesions (progressive plaques), in which ongoing myelin breakdown occurs in the absence of florid perivascular cell cuffing or other histological signs of acute inflammation, contribute to disease progression in cases of secondary-progressive multiple sclerosis.

Expression pattern of CXCR3, CXCR4, and CCR3 chemokine receptors in the developing human brain.

Chemokine receptors are essential components of the immune and central nervous systems, but little is known about their distribution during development. We evaluated the distribution of 3 chemokine receptors: CXCR3, CXCR4, and CCR3 in the human developing brain. Of these, CXCR3 was the only receptor expressed in fetal brain at 26 wk of gestation and its expression was restricted to glial cells, endothelial cells, and the choroid plexus. Neuronal staining was only seen at term in the Purkinje cells of the cerebellum. CCR3 appeared only at term in both neurons and glial cells. The expression pattern of these 2 receptors in the late gestation and term resembled that of adults. CXCR4 could not be detected in the fetal brain on neurons nor on glial cells. By examining pediatric cases, we determined that CXCR4 expression commences sometimes between 3.5 and 4.5 yr. Two of the chemokine receptors examined, CCR3 and CXCR4, can be used as co-receptor together with CD4 for HIV entry, but neither was expressed during the second trimester of pregnancy. Our findings suggest that it is unlikely that CCR3 or CXCR4 play a major role in HIV-1 transmission in the fetal brain before 37 wk of gestation.

Neuronal fractalkine expression in HIV-1 encephalitis: roles for macrophage recruitment and neuroprotection in the central nervous system.

HIV-1 infection of the brain results in chronic inflammation, contributing to the neuropathogenesis of HIV-1 associated neurologic disease. HIV-1-infected mononuclear phagocytes (MP) present in inflammatory infiltrates produce neurotoxins that mediate inflammation, dysfunction, and neuronal apoptosis. Neurologic disease is correlated with the relative number of MP in and around inflammatory infiltrates and not viral burden. It is unclear whether these cells also play a neuroprotective role. We show that the chemokine, fractalkine (FKN), is markedly up-regulated in neurons and neuropil in brain tissue from pediatric patients with HIV-1 encephalitis (HIVE) compared with those without HIVE, or that were HIV-1 seronegative. FKN receptors are expressed on both neurons and microglia in patients with HIVE. These receptors are localized to cytoplasmic structures which are characterized by a vesicular appearance in neurons which may be in cell-to-cell contact with MPs. FKN colocalizes with glutamate in these neurons. Similar findings are observed in brain tissue from an adult patient with HIVE. FKN is able to potently induce the migration of primary human monocytes across an endothelial cell/primary human fetal astrocyte trans-well bilayer, and is neuroprotective to cultured neurons when coadministered with either the HIV-1 neurotoxin platelet activating factor (PAF) or the regulatory HIV-1 gene product Tat. Thus focal inflammation in brain tissue with HIVE may up-regulate neuronal FKN levels, which in turn may be a neuroimmune modulator recruiting peripheral macrophages into the brain, and in a paracrine fashion protecting glutamatergic neurons.

Expression of caspase-3 in brains from paediatric patients with HIV-1 encephalitis.

Apoptosis of neurones, macrophages, and microglia occurs in the brains of paediatric patients with human immunodeficiency virus (HIV) type 1 encephalitis, which is often associated with pre-mortem neurological disease (progressive encephalopathy). We have previously reported that TUNEL-positive neurones in brain tissue from paediatric patients with HIV type 1 encephalitis and progressive encephalopathy are strikingly devoid of the pro-apoptotic gene product Bax, in marked contrast to brain-resident macrophages and microglia. Using immunocytochemical methods, the present study demonstrate that neurones in patients with HIV type 1 encephalitis and progressive encephalopathy, as well as macrophages and microglia, but not astrocytes, overexpress caspase-3, a pro-apoptotic enzyme that is proteolytically activated downstream of Bax-Bcl-2 dysregulation. Co-localization of neuronal cytoplasmic caspase-3 and nuclear TUNEL staining, a marker for fragmented DNA, was also infrequently observed in brain tissue from patients with HIV type 1 encephalitis and progressive encephalopathy. These findings suggest that vulnerable neurones in brain tissue from patients with HIV virus type 1 encephalitis and progressive encephalopathy undergo apoptosis by a mechanism that involves upregulation of caspase-3 in a pathway that is independent of Bax-Bcl-2 dysregulation. Furthermore, caspase-3 upregulation in apoptotic neurones likely occurs prior to DNA fragmentation.

Hemorrhagic chondroid chordoma mimicking pituitary apoplexy.

We describe a hemorrhagic chondroid chordoma involving the sella turcica with suprasellar extension. The CT and MRI appearances mimiked a hemorrhagic pituitary adenoma. Chondroid chordoma is a variant composed of elements of both chordoma and cartilaginous tissue. An uncommon bone neoplasm, located almost exclusively in the spheno-occipital region, it is usually not considered in the differential diagnosis of a tumor with acute hemorrhage in the sellar region. We discuss the clinical and radiological characteristics which may allow one to differentiate chondroid chordoma from other tumors of this area.

Surveillance for Creutzfeldt-Jakob disease among persons with hemophilia.

BACKGROUND: Although Creutzfeldt-Jakob disease (CJD) has been shown to be transmissible through blood components in rodent models, no human blood-to-blood transmission has been documented. If blood transmission were possible in humans, persons with hemophilia in the United States would be at higher risk of contracting CJD, because they receive large numbers of blood components. Nearly one-half of the hemophilia population contracted HIV in the 1980s, and many of these people have since died with neurologic complications. This study investigated whether some hemophilia patients with neurologic disorders may have died with CJD. STUDY DESIGN AND METHODS: Hemophilia treatment Centers across the United States were invited to participate in this retrospective surveillance study. The centers were asked to send any available formalin-fixed paraffin block brain samples from hemophilia decedents. Slides were prepared at the Centers for Disease Control and Prevention and reviewed by three expert neuropathologists. Two slides were stained for the prion protein at the request of one of the neuropathologists. RESULTS: Specimens from 24 decedents with genetic bleeding disorders were collected and reviewed.The panel found no evidence of CJD in any of the specimens. CONCLUSIONS: Although the study sample is small, these results support the growing evidence that CJD is not being transmitted in the nation's blood supply.

Clinical manifestations of mitochondrial DNA depletion.

OBJECTIVE: We studied five new patients with mitochondrial DNA (mtDNA) depletion to better define the clinical spectrum of this disorder. BACKGROUND: mtDNA depletion has been associated with myopathy or hepatopathy, or both, in infants and young children. Involvement of the CNS and peripheral nervous system has not been clearly established. METHODS: We reviewed the clinical course and performed morphologic, biochemical, and genetic analyses of muscle samples from five patients. RESULTS: Age at onset ranged from 3 months to 5 years, and one patient survived until age 10 1/2 years. Two patients had laboratory and clinical features reminiscent of dystrophinopathy, two had evidence of brain involvement, and two had peripheral neuropathy. Muscle biopsy specimens in all patients showed abundant ragged-red fibers. Biochemistry showed cytochrome c oxidase deficiency in all patients tested and decreased activities of other respiratory chain complexes in some. CONCLUSIONS: Inheritance appeared to be autosomal recessive, suggesting that mutations in nuclear DNA are responsible for mtDNA depletion. mtDNA depletion should be considered in children with mitochondrial disorders of uncertain etiology, and criteria for diagnosis are proposed.

HIV-associated brain pathology: a comparative international study.

Little is known about the frequency and variation of HIV-associated brain pathology in different geographical centres. To assess whether there is an association between the frequency of disease and demographic factors we examined the neuropathological findings in four European and two American cities. The cities included London, Edinburgh, Paris, Budapest, Baltimore and Newark. Information was collected on a total of 1144 cases. HIV encephalitis was the most common observation in all the centres. although its frequency varied between them (P < 0.01). Furthermore, there were significant differences (P < 0.001) between the various categories of exposure and the frequency of HIV encephalitis in Edinburgh and other centres. The occurrence of toxoplasmosis, progressive multifocal leukoencephalolpathy (PML) and cryptococcal infection also differed between the various centres (P < 0.01). None of the findings was attributable to age, sex, or ethnic origin, but the introduction of anti-retroviral treatment, such as Zidovudine, may have been important. Overall, this study highlights geographical variability and the potential importance for group of exposure and anti-retroviral medication as factors affecting the development of various HIV-associated brain lesions.

A neuronal and neuroanatomical correlate of HIV-1 encephalopathy relative to HIV-1 encephalitis in HIV-1-infected children.

Progressive central nervous system dysfunction analogous to the AIDS dementia complex (ADC) seen in adults (HIV-1-associated progressive encephalopathy or HIV-1 encephalopathy) commonly occurs in HIV-1-infected children. The cause appears to be directly or indirectly related to HIV-1, rather than to other opportunistic pathogens. The exact mechanism(s) by which the virus affects brain function is not known. To determine whether the virus might modify brain function via an alteration in cortical neurons, we examined peptide neurotransmitter expression in the frontal cortex of HIV-1-infected cases with clinical HIV-1 encephalopathy relative to pathologic HIV-1 encephalitis. In situ hybridization was used to determine the level of peptide neurotransmitter expression of somatostatin in the frontal cortex of cases with and without HIV-1 encephalopathy and/or HIV-1 encephalitis. A 2-fold higher number of preprosomatostatin mRNA-positive interneurons was present in layer IV of cases with HIV-1 encephalitis compared with cases without HIV-1 encephalitis. In cases with PE, this neuronal alteration was 4- to 5-fold higher than in cases without PE, and was present in subcortical white matter in addition to layer IV. In cases having both PE and HIV-1 encephalitis, and in cases with HIV-1 encephalitis alone, these neuronal alterations in layer IV and/or subcortical white matter related to disseminated microglial nodules, even when these potentially viral-infected cells were negative for HIV-1 p24 antigen, a marker of productive viral infection. An alteration in preprosomatostatin mRNA-expressing cells occurring with HIV-1 encephalitis may be at least one mechanism that contributes to HIV-1 encephalopathy. When compared with other cortical laminae, layer IV receives most of its synaptic input from the mediodorsal nucleus of the thalamus. Neurons in the subcortical white matter project to the thalamus. The thalamus has been shown to have high amounts of viral antigen and increased metabolic activity in patients with AIDS. An alteration in preprosomatostatin mRNA-expressing cells may play a role in HIV-1 encephalopathy.

Expression of pro- and anti-apoptosis gene products in brains from paediatric patients with HIV-1 encephalitis.

We have previously demonstrated the presence of DNA fragmentation in neurons, macrophages and microglia consistent with apoptosis, but not in reactive astrocytes in brain tissue from paediatric patients with HIV-1 encephalitis (HIVE). To further understand the underlying mechanism(s) for these findings as they relate to gene-directed neural cell death, we studied the in-situ expression of the Bcl-2 family of proteins, including the pro-apoptosis gene product Bax, the anti-apoptosis gene product Bcl-2, and Bcl-x. We demonstrate significantly elevated numbers of Bax-positive microglia and macrophages immunoreactive in basal ganglia and cerebral cortex of children who had HIVE, in comparison to HIV-1 infected children without encephalitis or children who were seronegative for HIV-1. In contrast, patients with HIVE, but not HIV-1 without encephalitis, or seronegative controls, had increased expression of Bcl-2 and Bcl-x in reactive astrocytes in cortex and basal ganglia. In vitro studies using Western blot analysis demonstrated an up-regulation in the levels of Bax, and phosphorylated (i.e. inactive) Bcl-2 in HIV-1 infected macrophages, and in LPS-activated macrophages, relative to levels in virus-negative unstimulated macrophages. These results suggest that productive HIV-1 infection, or cellular activation, renders macrophages more vulnerable to apoptosis. Taken together, these findings suggest that brain-resident macrophages and microglia in patients with HIV-1 encephalitis are more prone to undergo apoptosis and that astrocytes in contrast may be resistant to apoptosis. This may represent a mechanism to limit microglial activation and the spread of productive HIV-1 infection in the CNS of children with HIV-1 encephalitis.

In situ amplification and detection of HIV-1 DNA in fixed pediatric AIDS brain tissue.

To examine whether latent infection by HIV-1 occurs in the central nervous system, we optimized a procedure for amplification and detection of HIV-1 DNA in situ, in formalin-fixed brain tissue from a child with severe HIV-1-associated progressive encephalopathy and severe HIV-1 encephalitis. By the use of a two-step technique, which involved polymerase chain reaction with incorporation of digoxigenin-labeled nucleotides followed by in situ hybridization with biotinylated probes, we found infection of numerous mononuclear cells and astrocytes in the cerebral white matter as well as of perineuronal satellite cells in basal ganglia, but not of neurons. Following PCR amplification, nuclear signal was found in 10 to 20 times as many cells as in parallel, control experiments using conventional, unamplified in situ hybridization.

Preoperative MRI diagnosis of Lhermitte-Duclos disease: case report with associated enlarged vessel and syrinx.

BACKGROUND: The most common primary cerebellar tumor is hemangioblastoma, a lesion which is associated with magnetic resonance imaging (MR)-detectable vascularity in over 60%. Lhermitte-Duclos disease is an uncommon cause of a cerebellar mass that is not typically vascular. METHODS: Computed tomography (CT), MRI with and without contrast, and magnetic resonance venography was performed in a patient with a cerebellar mass. RESULTS: The cerebellar mass was noted to have a prominent vessel, as well as an associated syrinx. In spite of MRI-detectable vascularity, the striped appearance of the lesion was felt to be typical of Lhermitte-Duclos disease. At surgery, the mass was resected and the diagnosis of Lhermitte-Duclos disease was confirmed. CONCLUSIONS: The diagnosis of Lhermitte-Duclos disease should be made when MRI shows a parallel linear "tiger-striped" lesion of the cerebellum. The presence of an enlarged vessel and/or syrinx should not deter one from making the preoperative diagnosis.

Mechanisms for the transendothelial migration of HIV-1-infected monocytes into brain.

HIV-1 penetration of the brain is a pivotal event in the neuropathogenesis of AIDS-associated dementia. The establishment of productive viral replication or up-regulation of adhesion molecule expression on brain microvascular endothelial cells (BMVEC) could permit entry of HIV into the central nervous system. To investigate the contribution of both, we inoculated primary human BMVEC with high titer macrophage-tropic HIV-1 or cocultured them with virus-infected monocytes. In both instances, BMVEC failed to demonstrate productive viral replication. Cell to cell contact between monocytes and microvascular endothelium resulted in E-selectin expression on BMVEC. BMVEC. cocultured with LPS-activated HIV-infected monocytes expressed even higher levels of E-selectin and vascular cell adhesion molecule-1 (VCAM-1). Transwell assays supported a role of soluble factors, from virus-infected monocytes, for the induction of adhesion molecules on BMVEC. To verify the in vivo relevance of these findings, levels of adhesion molecules were compared with those of proinflammatory cytokines and HIV-1 gene products in brain tissue of AIDS patients with or without encephalitis and HIV-seronegative controls. E-Selectin, and to a lesser degree VCAM-1, paralleled the levels of HIV-1 gene products and proinflammatory cytokines in brain tissue of subjects with encephalitis. Most importantly, an association between macrophage infiltration and increased endothelial cell adhesion molecules was observed in encephalitic brains. Monocyte binding to encephalitic brain tissue was blocked with Abs to VCAM-1 and E-selectin. These data, taken together, suggest that HIV entry into brain is, in part, a consequence of the ability of virus-infected and immune-activated monocytes to induce adhesion molecules on brain endothelium.

Activation of nuclear factor kappa B in brains from children with HIV-1 encephalitis.

Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system is associated with decreased neuronal density in discrete areas of the brain. Neuronal loss may occur via apoptosis, initiated by soluble neurotoxic factors secreted from HIV-1 infected macrophages and microglia. To examine further the molecular events involved in HIV-1 neuropathogenesis, we assessed the activity of NF kappa B, an inducible transcription factor involved in the activation of multiple proinflammatory, and potentially neurotoxic, genes. NF kappa B was analysed by immunocytochemistry using specific antisera to the NF kappa B p. 50 and p. 65 subunits. Brains from children with HIV-1 encephalitis and progressive encephalopathy were found to contain increased numbers of NF kappa B immunoreactive cells, relative to control brains (HIV-1 negative, or HIV-1 positive without encephalitis). Double-labelling studies using antibodies to CD68, or RCA-1 lectin, markers for cells of monocyte/macrophage lineage, revealed an increase in the number of microglia and macrophages with nuclear immunoreactivity for NF kappa B in association with HIV-1 encephalitis. NF kappa B positive multinucleated giant cells were also detected, as were cells which contained both NF kappa B and HIV-1 antigen. In contrast, the number of neurons and GFAP-positive astrocytes that were immunoreactive for NF kappa B was approximately the same in all groups of subjects. These data are consistent with the hypothesis that persistent, high-level activation of NF kappa B may promote the sustained production of neurotoxins by microglia and macrophages during HIV-1 encephalitis.

Apoptotic neurons in brains from paediatric patients with HIV-1 encephalitis and progressive encephalopathy.

The pathogenesis of human immunodeficiency virus type 1 (HIV-1) associated dementia in adults involves neuronal loss from discrete areas of the neocortex and subcortical regions, but the mechanism for neuronal death is poorly understood. Gene-directed cell death resulting in apoptosis is thought to be a normal feature of neuronal development, but little is known about neuronal apoptosis in disease states. We investigated whether HIV-1 infection of the central nervous system is spatially associated with apoptosis of neurons. Using an in situ technique to identify newly cleaved 3'-OH ends of DNA as a marker for apoptosis, we demonstrate the presence of apoptotic neurons in cerebral cortex and basal ganglia of children that had HIV-1 encephalitis with progressive encephalopathy. Furthermore, an association was observed between the localization of apoptotic neurons and perivascular inflammatory cell infiltrates containing HIV-1 infected macrophages and multinucleated giant cells. Apoptotic neurons and p24-positive macrophages were observed infrequently in cerebral cortex and basal ganglia in children with HIV-1 infection without encephalitis or clinical encephalopathy. In nine control (HIV-1 negative) brains, ranging from the first post-natal month of life to 16.5 years of age, infrequent neuronal apoptosis was observed in three cases. These findings suggest that neuronal apoptosis is unlikely to be associated with post-natal development except in early post-natal germinal matrix, and that it may instead represent the end result of specific pathological processes, such as HIV-1 encephalitis.

Cellular localization of human herpesvirus-6 in the brains of children with AIDS encephalopathy.

Human herpesvirus-6, the etiologic agent of exanthem subitum, is a ubiquitous virus that infects almost all children by the age of 2 years and that has previously been shown to be neuroinvasive. These characteristics suggest that human herpesvirus-6 may be important in the neuropathogenesis of acquired immune deficiency syndrome (AIDS) in children. To address this hypothesis, we evaluated postmortem pediatric brain tissues for the presence of human herpesvirus-6 infection. Using in situ hybridization with a digoxigenin-labeled DNA probe for the large tegument protein gene of human herpesvirus-6, we detected nuclear signals in postmortem brain tissue from 4/5 children with human immunodeficiency virus-1 encephalitis. Human herpesvirus-6 DNA was found in numerous oligodendrocytes of the white matter and less frequently in astrocytes, macrophages, microglia and neurons. The human herpesvirus-6 positive cells detected by in situ hybridization were not immunoreactive either for human herpesvirus-6 early nuclear phosphoproteins or for surface glycoproteins associated with productive infection. Only rare human herpesvirus-6 infected cells were found in age-matched control brain tissues. No human herpesvirus-6 infected cells were found in human fetal brain tissue. These data suggest that human herpesvirus-6 is more extensively disseminated in neural cells in the presence of human immunodeficiency infection and immunodeficiency in pediatric AIDS patients, and it may contribute to the pathogenesis of AIDS encephalopathy.

Neurological manifestations of perinatally acquired HIV-1 infection.

Infection with the human immunodeficiency virus type 1 (HIV-1) remains a major potential cause of neurological disorders in children and adults throughout the world. This article provides an overview regarding the epidemiology, clinical manifestations, and neuropathogenesis of perinatally acquired HIV-1 infection. Insights regarding the mechanisms of neuroinvasion and neuropathogenesis may allow novel strategies for treating or preventing the devastating consequences of HIV-1 infection of the central nervous system (CNS).