Advances in neuroimmunology最新文献

Many studies have examined the relationship between stress and immunity, however, only a few have explored associations between stress and Immoral immunity. In our review of this literature, three ways of characterizing the response of the humoral immunity system to stress were identified: total immunoglobulins, antibody to latent viruses and antibody to vaccines. These studies provide some support for the hypothesis that stress affects humoral immunity, particularly response to latent virus, but further research is required to confirm these observations. Several directions for future research are proposed.

We have demonstrated that human brain capillary endothelial (HBCE) cells, unlike umbilical or aortic endothelial cells are permissively infected by HIV. HIV infection of HBCE cells is noncytolytic and is mediated by a CD4- and GalCer-independent mechanism, implying that HBCE cell tropic strains utilize a unique receptor. The V3 loop of gp120 appears to be important in this reaction. T-cell tropic but not brain-derived macrophage tropic HIV strains selectively infect brain endothelium suggesting that T-cell tropism is important for HIV entry through the blood-brain barrier (BBB). The ability of HIV to infect cells that compose the BBB implies that the virus may be directly involved in the BBB dysfunction observed in

AIDS patients. HIV infection of HBCE cells may allow the flow of cytokines or toxic metabolites from the circulating blood into the brain parenchyma either by disrupting tight junctions or by altering the ability of the cells to regulate transport of substances across the BBB by transcytosis. HIV infection may also result in endothelial cell-induced astrocytosis by release of cytotoxic substances or modulation of abluminal surface antigens which contact astrocytic foot processes. Finally, HIV infection of the brain endothelium could facilitate virus entry to the CNS either by infection of HBCE cells or via entry of HIV-infected leucocytes. The establishment of our in vitro HIV-HBCE cell system will allow us to explore the potential mechanisms which mediate AIDS dementia.

The pathogenesis of the acquired immuno-deficiency syndrome (AIDS) dementia complex (ADC) is unknown. However, recent work indicates that neurons and astrocytes are functionally compromised by exposure to viral components or cellular factors released from HIV-1-infected macrophages/microglia. We show that exposure of primary cultured rat astrocytes to the major HIV envelope glycoprotein gp120 results in alterations of ion and solute transport that may contribute to neuronal cell injury.

This review aims to summarize recent work related to the pathogenesis and possible treatment of neuronal injury in the acquired immunodeficiency syndrome (AIDS), especially with reference to potential neurotoxic substances released by HIV-infected or gp120-stimulated macrophages/microglia. Approximately a third of adults and half of children with AIDS eventually suffer from neurological manifestations, including dysfunction of cognition, movement, and sensation. Among the various pathologies reported in brains of patients with AIDS is neuronal injury and loss. A paradox arises, however, because neurons themselves are for all intents and purposes not infected by human immunodeficiency virus type 1 (HIV-1). This paper reviews recent evidence suggesting that at least part of the neuronal injury observed in the brains of AIDS patients is related to excessive influx of Ca²⁺ after the release of potentially noxious substances from HIV-infected or gp120-stimulated macrophages/microglia.

There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or demise of neurons via a potentially complex web of interactions between macrophages (or microglia), astrocytes, and neurons. HIV-infected monocytoid cells (macrophages, microglia or monocytes), especially after interacting with astrocytes, secrete substances that potentially contribute to neurotoxicity. Not all of these substances are yet known, but they may include eicosanoids, i.e. arachidonic acid and its metabolites, as well as platelet-activating factor. Other candidate toxins include nitric oxide (NO·), superoxide anion (02·⁻), and the N-methyl-scd-aspartate (NMDA) agonist, cysteine. Similarly, macrophages activated by HIV-1 envelope protein gp120 also appear to release arachidonic acid and its metabolites, and cysteine. These factors can lead to increased glutamate release or decreased glutamate re-uptake. In addition, interferon-γ (IFN-γ) stimulation of macrophages induces release of the NMDA-like agonist, quinolinate. HIV-infected or gp120-stimulated macrophages also produce cytokines, including TNF-α and ILI-β, which contribute to astrocytosis. A final common pathway for neuronal susceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, neuropathic pain and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage-dependent Ca²⁺ channels and NMDA receptor-operated channels with resultant generation of free radicals, and therefore offers hope for future pharmacological intervention.

Continuous intravenous administration of zidovudine (AZT) has been reported to improve cognitive function in HIV-infected pediatric patients (Pizzo et al., 1988). The effects of long-term zidovudine treatment in the perinatally infected pediatric population, including antiviral efficacy and effects on cognitive and motor function has not been systematically examined. These questions were addressed in rhesus macaque infants infected at birth with SIV_SMM/B670, a primate model for infantile HIV infection and disease (Eiden et al., 1993a). Continuous or intermittent administration of AZT during the first 6 months following infection resulted in about a doubling of lifespan, a delay in the occurrence of motor impairment, and lower virus burden and quinolinic acid levels in cerebrospinal fluid (CSF) following administration of the antiviral drug.

In order to detect latent infection in neurons or other cell types in formalin-fixed brain tissue, we performed polymerase chain reaction amplification with incorporation of digoxigenin-conjugated deoxynucleotides, followed by in situ hybridization with biotinylated probes. The use of this two-step technique in brain tissue from a child with severe HIV-1 encephalitis revealed signal in both nuclear and perinuclear regions of cells identified as monocytes and astrocytes, and also in perineuronal satellite cells of glial morphology, but HIV-1 infection of neurons was not detected.