Katsuhiro Kure

Human immunodeficiency virus-1 infection of the nervous system: An autopsy study of 268 adult, pediatric, and fetal brains

The central nervous system (CNS) of 221 adults and 31 infants or children with the acquired immunodeficiency syndrome (AIDS) was examined with immunocytochemistry for infectious agents and for human immunodeficiency virus-1 (HIV-1) antigen (gp41). Since the major risk factor in this population was intravenous drug abuse, there were more female and pediatric patients than in other neuropathology autopsy series. Although children had a different spectrum of pathologic changes, including less frequent opportunistic infections, women did not differ from men in terms of types or incidence of opportunistic infections, vascular disease, neoplasia, and subacute AIDS encephalitis (SAE). Subacute AIDS encephalitis was detected in 26% of adult and 48% of pediatric brains. Immunocytochemical analysis of 100 adult and 20 pediatric brains revealed gp41 immunoreactivity in 78% and 40%, respectively. Virtually all adult brains with SAE had gp41 immunoreactivity in macrophages and microglia. Even brains with no significant pathology had frequent gp41 immunoreactivity, especially in the basal ganglia. In pediatric brains, including cases with SAE, gp41 immunoreactivity was less abundant, suggesting the possibility of latent infection or viral clearance. Spinal cords with vacuolar myelopathy or corticospinal tract degeneration had only rare gp41-positive cells. Brains from 16 aborted fetuses from HIV-1-seropositive women were all negative for gp41 immunoreactivity, but 12 brains were positive for HIV-1 by the polymerase chain reaction. These results may indicate that HIV-1 infection in fetal brains is below the limits of detection of immunocytochemistry. The differences noted between adults and children suggest that adults more often have productive CNS HIV-1 infection.

Morphology and distribution of HIV-1 gp41-positive microglia in subacute AIDS encephalitis. Pattern of involvement resembling a multisystem degeneration.

SummaryAmong 100 brains from patients with acquired immunodeficiency syndrome (AIDS), 33 brains (21 adults and 12 children) with histological evidence of subacute AIDS encephalitis were immunostained with one of the most sensitive antibodies to HIV-1 antigen, anti-gp41. Twenty-six (20/21 adults, 6/12 children) of the 33 brains showed pg41 positivity. Brains from children had fewer gp41-positive cells than brains from adults. The distribution of gp41-positive cells was characteristic. They were frequently detected and most numerous in the globus pallidus (medial > lateral). Although gp41-positive cells were prevalent, fewer were detected in the corpus striatum and thalamus. Of infratentorial areas involved, the ventral midbrain, especially the substantia nigra, and the dentate nucleus contained many positive cells. Lower levels of infections, often patchy, were noted in the cerebral and cerebellar white matter and pontine base. Gp41-positive cells were rarely seen in the cerebral cortex, medulla, spinal cord, leptomeninges, choroid plexus, ependyma, subependymal areas and endothelia. Besides immunoreactive macrophages and multinucleated cells, gp41-positive microglia with various morphological alterations were abundant in the deep cerebral gray matter, ventral midbrain and dentate nucleus. Most of these microglia were undetectable with conventional histological methods. We discuss the significance of the distribution of HIV-1-infected cells, especially microglia, with respect to cellular tropism and involvement of deep gray matter nuclei in a pattern reminiscent of a multisystem atrophy.

Detection of HIV in fetal central nervous system tissue

Neurological disease is a common finding in children with AIDS and in others without signs of disease but with evidence of congenital HIV-1 infection. To investigate the possibility that HIV-1 can infect fetal central nervous system (CNS) tissue and therefore possibly serve as the substrate for the abnormal neurodevelopment characteristic of pediatric AIDS, eight abortus CNS samples (one set of twins) from seven HIV-1-seropositive intravenous drug users (IVDUs) and eight control abortus CNS samples from eight HIV-1-seronegative IVDUs were analyzed for HIV-1 infection. HIV-1 nucleic acid was detected only after the use of polymerase chain reaction (PCR) in three of eight CNS samples from HIV-seropositive IVDUs but not in samples from seronegative subjects. In situ hybridization confirmed that HIV-1 DNA sequences were in cells in the CNS parenchyma of two of the three positive samples. This study demonstrates that HIV-1 can infect human fetal CNS tissue in vivo, but that the use of PCR may be necessary for its detection.

Immunohistochemical Localization of an Hiv Epitope in Cerebral Aneurysmal Arteriopathy in Pediatric Acquired Immunodeficiency Syndrome (AIDS)

A 6-year-old boy with acquired immunodeficiency syndrome (AIDS) developed aphasia and quadriplegia 3 months before his death. Cerebral vascular ectasia and multiple cerebral infarcts were noted on premortem radiological studies. Postmortem evaluation revealed diffuse aneurysmal dilatation of the circle of Willis associated with fresh and organizing thrombi, destruction of the elastic lamina, and marked intimal fibroplasia. Multiple cerebral infarcts and subacute AIDS encephalitis with basal ganglia calcification were also present. Immunohistochemistry with a monoclonal antibody (anti-gp41) to human immunodeficiency virus (HIV) demonstrated positively stained cells in the arterial wall of the circle of Willis and in the cerebral parenchyma. Double immunostaining demonstrated that gp41-positive cells in the circle of Willis were also positive for a macrophage marker or leukocyte-common antigen, but not with an endothelial marker. Some macrophages or microglia in the cerebrum were also colabeled with anti-gp41. These results suggest that HIV may be directly involved in vascular pathology associated with pediatric AIDS.

Unusual patterns of Histoplasma capsulatum meningitis and progressive multifocal leukoencephalopathy in a patient with the acquired immunodeficiency virus.

Disseminated histoplasmosis (DH) and progressive multifocal leukoencephalopathy occur in acquired immunodeficiency syndrome (AIDS). At autopsy, DH patients with central nervous system involvement almost always show extensive involvement of the lungs and reticuloendothelial system in addition to the brain, and progressive multifocal leukoencephalopathy is manifest as multiple demyelinating lesions in several locations in the brain. We describe an AIDS patient with a long history of aggressively treated DH who died with DH in the brain only; fungus was not found elsewhere at autopsy. In addition, there was a papovavirus infection restricted to the cerebellum with predominant involvement of the internal granular cell layer; again, demyelinating lesions were not found elsewhere in the brain. Each of these patterns of brain involvement is rare. As the incidence of AIDS increases and patients are treated aggressively, the frequency of unusual neuropathologic patterns of opportunistic infections may be expected to increase.