An experimental model system for HIV-1-induced brain injury.
The pathological hallmark of HIV infection in brain is productive viral replication in cells of mononuclear phagocyte lineage including brain macrophages, microglia and multinucleated giant cells (Koenig et al., 1986; Wiley et al., 1986; Gabuzda et al., 1986; Stoler et al., 1986). These cells secrete viral and cell encoded neurotoxins that lead to neuronal injury, glial proliferation and myelin pallor during advancing disease (Genis et al., 1992; Giulian et al., 1990, 1993; Pulliam et al., 1991). The apparent paradox between the distribution and numbers of virus infected cells and brain tissue pathology support indirect mechanisms for CNS damage (Epstein, 1993; Geleziunas et al., 1992; Merrill and Chen, 1992; Michaels et al., 1988; Price et al., 1988). First, brain macrophages and microglia can produce neurotoxins by secretion of viral proteins (for example, gp120) (Dawson et al., 1991; Merrill et al., 1989; Lipton et al., 1990; Lipton, 1993). Second, HIV primes macrophages for immune activation to produce neurotoxins including: cytokines (TNF alpha and IL-1 beta), eicosanoids: quinolinate and nitric oxide (NO). Chronic immune stimulation mediated by opportunistic infections and chronic interferon gamma (IFN gamma) production (in and outside the CNS) continues the process of macrophage activation leading to progressive neural injury. The hyperresponsiveness of HIV-infected macrophages to activation results in production of cellular factors that activate uninfected macrophages. This suggests that HIV-infected macrophages are both perpetrators and amplifiers for neurotoxic activities.
Gendelman
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Department of Medicine, University of Nebraska Medical Center, Omaha 68198.
Genis
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Jett
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Zhai
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QH
Nottet
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D015526:AIDS Dementia Complex / Q000473:pathology; D001253:Astrocytes / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism; D018792:Encephalitis, Viral / Q000821:virology; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism / Q000821:virology; D017628:Microglia / Q000378:metabolism / Q000821:virology; D008954:Models, Biological; D009474:Neurons / Q000473:pathology
D016207:Cytokines; D015777:Eicosanoids