Neuropathology and pathogenesis of SIV infection of the central nervous system.
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AIDS Dementia Complex↗
Biomedical subjects
L R Sharer
Publications and source records attributed to L R Sharer.
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).
AIDS Dementia Complex↗
Multiple sclerosis: remyelination of nascent lesions.
The relationship between plaque pathology and disease duration was examined in 15 patients with multiple sclerosis who died early in the course of their illness. Myelin-stained sections revealed that most plaques examined in patients who died during the first month of their illness showed evidence of ongoing myelin destruction accompanied by a loss of oligodendrocytes. Plaques containing large numbers of oligodendrocytes were not observed in these patients, but were relatively common in patients who died more than 1 month after clinical onset. Remyelination affecting more than 10% of the plaque area was observed in 3 of 82 plaques in 5 patients who died within 10 weeks of clinical onset, in 38 of 105 plaques in 5 patients who died 3 to 10 months after clinical onset, and in 19 of 92 plaques in 5 patients who died 18 months or longer after clinical onset. The study provides new evidence that both oligodendrocytes and myelin are destroyed in new lesions, that this activity ceases completely in many lesions within a few weeks, and that remyelination frequently ensues following repopulation of the plaque by oligodendrocytes. The findings suggest that new lesions normally remyelinate unless interrupted by recurrent activity and that remyelinated shadow plaques are the outcome of a single previous episode of focal demyelination.
Adolescent↗
Multifocal necrotizing leukoencephalopathy with pontine predilection in immunosuppressed patients: a clinicopathologic review of 16 cases.
Multifocal necrotizing leukoencephalopathy (MNL) is characterized by multiple, usually microscopic, foci of necrosis confined primarily to the white matter of the basis pontis, but sometimes found elsewhere in the central nervous system. All 16 patients in whom we identified MNL had underlying immunosuppression, either naturally occurring or iatrogenic, including the acquired immunodeficiency syndrome (seven patients), acute leukemias (four patients), and lymphoma (one patient). One patient each had severe combined immunodeficiency, orthotopic liver transplantation, Shwachman-Diamond syndrome, and idiopathic thrombocytopenic purpura treated with high-dose steroids. Histologically, lesions of MNL show demyelination, spongiosis, axonal swelling, minimal histiocytic infiltrates, and frequent axonal calcification. Multifocal necrotizing leukoencephalopathy lesions were found in the pons of all patients, most commonly in the crossing pontocerebellar fibers, but often in the descending white matter tracts and rarely in the tegmentum. Three cases also showed nonpontine foci of MNL involving the white matter of the medulla, cerebellum, and cerebral hemispheres. Multifocal necrotizing leukoencephalopathy is a distinct entity usually localized to the basis pontis and is most consistently associated with immunosuppression, but as yet lacks other clearly defined clinical correlates.
Adult↗
Cognitive and motor impairments associated with SIV infection in rhesus monkeys.
Cognitive and motor deficits are now recognized as significant clinical features of infection with the human immunodeficiency virus (HIV). Juvenile rhesus macaques infected with simian immunodeficiency virus (SIV) were found to exhibit cognitive and motor deficits characteristic of HIV infection. Impairment on a motor skill task was the most reliable indicator of infection. Various cognitive impairments were also evident. These deficits were related to SIV infection of the brain but not to inflammatory lesions at a particular locus. The results suggest that the SIV-infected rhesus macaque is a valuable model for understanding the cause of HIV-associated central nervous system dysfunction and for developing a treatment.
Animals↗
Meningitis due to Prototheca wickerhamii in a patient with AIDS.
The first documented case of algal meningitis due to Prototheca wickerhamii is reported in a patient with AIDS. The initial CSF culture yielded only Cryptococcus neoformans. P. wickerhamii was isolated on four subsequent lumbar punctures. The patient died, and at autopsy the alga was isolated from leptomeninges over the brain and about the spinal cord. Histologic sections from numerous locations of the brain revealed masses of cryptococci and prototheca.
AIDS-Related Opportunistic Infections↗
Pathology of HIV-1 infection of the central nervous system. A review.
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AIDS Dementia Complex↗
Human immunodeficiency virus type 1 nef quasispecies in pathological tissue.
The role of the nef gene in human immunodeficiency virus type 1 (HIV-1) infection is poorly understood. To provide a basis for studies on the role of nef in AIDS, we used targeted polymerase chain reaction amplification and DNA sequencing to determine the structure of nef genes in pathologic tissue from HIV-1-infected children and adults. We find that the nef reading frame is open in 92% of clones derived from both brain and lymphocytic tissue of children, suggesting that nef is expressed in these tissues. One HIV-1 clone, BRVA, obtained by coculture from the brain of an adult AIDS patient with progressive dementia, was previously shown to contain a duplicated region in nef. We show here that similar duplications are widespread in both adults and children with AIDS. However, coculture strongly selects against the broad spectrum of nef quasispecies found in tissue. These findings suggest functional selection for nef quasispecies in pathologic tissues during HIV-1 infection of the human host.
Acquired Immunodeficiency Syndrome↗
HIV-1 V3 domain variation in brain and spleen of children with AIDS: tissue-specific evolution within host-determined quasispecies.
DNA coding for the principal neutralization epitope of HIV-1 (the V3 domain of the envelope glycoprotein gp120) was amplified by polymerase chain reaction from postmortem brain and spleen tissue of three perinatally infected children who died of AIDS with progressive encephalopathy. Sequences obtained directly (without cloning) from this DNA were compared with sequences of 52 molecular clones made from this DNA. Cluster analysis showed that V3 domain sequences from two of the three children were similar to sequences from the American MN/SC isolates, while those from one child were more closely similar to the Caribbean RF isolate. Comparison of sequences obtained directly with consensus sequences derived from cloned DNA showed that V3 sequences are characteristic for an individual host. In one child, the V3 sequence determined directly from brain DNA was very distant from the consensus brain clone sequence and from the spleen sequences, suggesting a diverging quasispecies distribution. Site-directed hybridization demonstrated that brain-specific sequences present in 33% of brain-derived clones were absent from clones derived from spleen. The evidence suggests that brain- and spleen-specific variants evolve independently within each host-delimited quasispecies.
Acquired Immunodeficiency Syndrome↗
Serial pathogenesis study of SIV brain infection.
A serial study of early SIV brain infection revealed initial involvement of leptomeninges, followed by perivascular infection of brain parenchyma. Severity of SIV encephalitis correlated with severity of systemic disease rather than with length of infection. Diffuse white matter disease was not observed, and there was little evidence of SIV infection of brain endothelial cells. SIV infection of leptomeninges is separate from infection of the brain, which appears to be due to transvascular spread of infected monocytes/macrophages.
Animals↗
Spinal cord disease in children with HIV-1 infection: a combined molecular biological and neuropathological study.
An autopsy study was performed on spinal cords from 18 children who died with HIV-1 infection, using standard histopathologic techniques as well as in situ hybridization and immunocytochemistry for HIV-1. Of 16 spinal cords examined by histology, nine had inflammatory cell infiltrates and six had multinucleated cells; both types of lesion are associated with the presence of HIV-1 in central nervous system tissue. HIV-1 type lesions were often present in the spinal cord and brain from the same patient. Pallor of myelin in corticospinal tracts in the cord was present in half of the cases; this change correlated with diffuse myelin pallor in the corresponding brains, but not with the HIV-1 associated changes in the cords. In situ hybridization for HIV-1 nucleic acid sequences gave positive results in seven of 18 spinal cords, with hybridizing signal usually localized to inflammatory cell infiltrates and multinucleated cells. Positive in situ hybridization, on frozen sections, correlated with the presence of HIV-1 associated changes on paraffin sections from the same cases. Immunocytochemistry for p25 core protein of HIV-1, using a monoclonal antibody on frozen sections, was positive in multinucleated cells, macrophages, and microglia. In this series there were two cases of vacuolar myelopathy, one a 30-month-old boy who had concomitant measles virus in the spinal cord grey matter, and the other nine-year-old girl who had severe HIV-1 infection of the cord. Other than the single case of measles virus, there were no opportunistic infections in the cords in this series. HIV-1 frequently involves the spinal cord in children with AIDS, while opportunistic infections are rare. Vacuolar myelopathy occurs in children with HIV-1 infection, although its occurrence is much less frequent than in adults with AIDS.
Acquired Immunodeficiency Syndrome↗
Interaction of astrocytes and newly formed oligodendrocytes in resolving multiple sclerosis lesions.
Cells resembling oligodendrocytes are sometimes seen within reactive astrocytes in fresh lesions in multiple sclerosis. Using immunostained paraffin and epoxy sections of fresh plaques obtained at autopsy from a series of cases of short clinical duration, it was found that small cells with round nuclei are commonly observed within reactive astrocytes in some hypercellular plaques and that these cells are phenotypically undifferentiated oligodendrocytes, i.e., nonmyelinating cells expressing intensely the oligodendrocyte determinants 2',3'-cyclic nucleotide 3'-phosphohydrolase and the carbohydrate epitope present on the family of cell adhesion molecules recognized by monoclonal antibody HNK-1. They also stain positively for IgG. This unusual astrocyte-oligodendrocyte interaction, which appears to be restricted to nonmyelinating oligodendrocytes in lesions of several weeks' to several months' duration, has not been described during normal oligodendrocyte differentiation or in experimental central remyelinating lesions. It bears some resemblance, however, to a pattern of slow oligodendrocyte destruction seen previously in organotypic perinatal central nervous tissue cultures exposed to multiple sclerosis serum. It is concluded that the evolution of some multiple sclerosis lesions early in the course of the disease is associated with abnormal binding and/or destruction of newly generated oligodendrocytes by reactive astrocytes. These observations raise new questions concerning mechanisms underlying failed remyelination in multiple sclerosis, including the novel possibility of an immune response directed against a developmentally restricted oligodendrocyte antigen.
2',3'-Cyclic Nucleotide 3'-Phosphodiesterase↗
Neuropathology of HIV infection: adults versus children.
The lower incidence of complicating opportunistic and reactivated latent infections in the CNS of children with HIV infection has resulted in a "cleaner" system, allowing better appreciation of the lesions associated with primary HIV brain infection. The most striking differences that we have seen in the CNS of children, when compared to adults with regard to primary HIV infection, have been the following: More florid inflammation and more frequent MGC in the children; more frequent localization of MGC in the cerebral cortex in children; more basophilic mineralization in the children; more perivascular brown pigment in the adults; and more obvious white matter changes in the adults. It has been noted that the median survival time for children under one year of age with AIDS is significantly less than that for older children (6.5 months vs. 19.7 months). Thus the tempo of HIV infection would seem to be more rapid in children, particularly young children. Our own neuropathological observations would support the hypothesis of a more fulminant CNS disease in children, in keeping with the well-known phenomenon of increased virulence of viral infections in the immature central nervous system.
Adult↗
Evaluation of an atypical HIV type 1 antibody. Serologic pattern leading to detection of HIV type 2 infection in North America.
The variability and discordance of human immunodeficiency virus type 1 (HIV-1) antibody enzyme immunoassay determinations on serial specimens derived, to our knowledge, from the first documented case of HIV-2 infection in North America are described. The initial specimen was weakly reactive, but two subsequent serum specimens were both nonreactive by enzyme immunoassay. All specimens were indeterminate for HIV-1 antibody by HIV-1 Western blot analysis. Serum HIV-2 antibody was demonstrated by enzyme immunoassay using whole virus lysate, HIV-2-specific synthetic peptide assays, and HIV-2 Western blot analysis. Human immunodeficiency virus type 2 genomic sequences were demonstrated in peripheral blood mononuclear cells using gene amplification technology. Human immunodeficiency virus type 2, isolated from peripheral blood lymphocytes, had typical morphologic features of lenti-virus by electron microscopy. Western blot analysis and other specific assays should be considered in individuals with clinical evidence suggesting HIV infection who are nonreactive for HIV-1 antibody by enzyme immunoassay or who have atypical reactivity patterns.
Acquired Immunodeficiency Syndrome↗
Neurological and neuropathological features of human immunodeficiency virus infection in children.
A progressive encephalopathy occurs in 30 to 50% of infants and children infected with the human immunodeficiency virus (HIV). The expression of HIV antigen in the cerebrospinal fluid appears to correlate with the clinical occurrence of progressive encephalopathy. The signs of progressive encephalopathy in children with HIV infection, including loss of developmental milestones, impaired brain growth, and progressive motor dysfunction, indicate a poor prognosis and almost invariably a fatal outcome. Neuropathological findings in these children, including virus-laden macrophages and multinucleated giant cells are unique to this condition. Opportunistic or reactivated latent infections and neoplasms of brain occur in children with HIV infection but are uncommon. These findings support the hypothesis that the progressive encephalopathy observed in HIV-infected children is caused by primary infection of the brain with this virus. Epidemiological data predict increasing numbers of HIV-infected women and children. Research aimed at an understanding of the mechanism(s) of mother-to-infant transmission of HIV infection is urgently needed so that strategies for the prevention and treatment of such infection in children may be planned.
Acquired Immunodeficiency Syndrome↗
Comparison of simian immunodeficiency virus and human immunodeficiency virus encephalitides in the immature host.
The simian immunodeficiency virus (SIV) is closely related to the human immunodeficiency virus (HIV) in genomic organization and morphology. More important, SIV and HIV are both primate lentiviruses that cause transmissible immunodeficiency and encephalitis, with an apparently increased virulence in the immature host. The neuropathological features in common between SIV encephalitis in juvenile macaque monkeys and HIV encephalitis in children include the invasion of brain with virus-laden macrophages, the formation of multinucleated (syncytial) giant cells, and white matter lesions and subtle white matter astrocytosis. Important differences include giant cell leptomeningitis and evidence of necrosis and karyorrhexis in brain macrophage infiltrates in SIV-infected monkeys. These changes probably represent a more acute inflammatory process. The importance of future studies to define pathogenetic features of SIV encephalitis, using molecularly characterized isolates with varying neurovirulence and host range, are emphasized.
Acquired Immunodeficiency Syndrome↗
Human immunodeficiency virus type 1 (HIV-1) infection of the nervous system: a review.
Human immunodeficiency virus type I (HIV-1) is associated with a spectrum of neurological disorders. At the time of primary HIV-1 infection, an acute aseptic meningitis or encephalitis indicates central nervous system invasion. Evidence of HIV-1 infection is found in the CSF of most asymptomatic seropositive individuals, suggesting viral persistence in the nervous system. After a long incubation period, viral activation is signaled by expression of HIV-1 antigen in the CSF, which correlates with a profound dementia in adults or with an analogous progressive encephalopathy in children. The neuropathological substrate of this dementing process consists of multinucleated giant cells and diffuse white matter pallor. Immunocytochemical and in situ hybridization studies demonstrate that antigen presenting cells, including blood derived macrophages and resident brain microglia, are directly infected by HIV-1, and participate in the formation of the syncytial giant cells. Astrocytes and endothelial cells may also be infected, but evidence for infection of oligodendroglia and neurons is lacking. Studies of lentiviral encephalitides in ungulates and non-human primates emphasize the importance of specific viral antigenic stimulation and the role of inflammatory cells as direct or indirect mediators of tissue damage. The disorders of the peripheral nervous system described in patients with HIV-1 infection have not been convincingly linked to direct viral infection. At least two of the neuromuscular complications, the inflammatory motor neuropathy and polymyositis are likely to have an autoimmune pathogenesis.
Acquired Immunodeficiency Syndrome↗
Congenital acquired immunodeficiency syndrome and congenital toxoplasmosis: pathologic support for a chronology of events.
We report a case of congenital acquired immunodeficiency syndrome (AIDS) with congenital opportunistic toxoplasmosis. The thymic histopathology was that seen in childhood AIDS cases and not that seen in primary congenital toxoplasmosis. The toxoplasma infection was selectively localized to the brain and the serum titers were paradoxically low as reported in most adult cases of AIDS with secondary infection by the parasite. These findings strongly suggest that the infection by the human immunodeficiency virus (HIV) preceded the toxoplasma infection in the fetus.
AIDS Serodiagnosis↗