Regulation of neural cell survival by HIV-1 infection.
Infection by the lentivirus, human immunodeficiency virus type 1 (HIV-1), results in a variety of syndromes involving both the central (CNS) and the peripheral (PNS) nervous systems. Productive HIV-1 infection of the CNS is chiefly detectable in perivascular macrophages and microglia. HIV-1 encoded transcripts and proteins have also been detected in the PNS; however, productive viral replication appears to be sparse and restricted to the macrophage cell population. Despite the absence of productive infection of neurons, HIV-1 infection has been associated with neuronal loss in distinct regions of the brain. Neuronal cell loss may occur through both necrosis and apoptosis, although neuronal apoptosis appears to be a feature of AIDS, as only rare apoptotic neurons have been demonstrated in a few pre-AIDS cases. Although there is no clear consensus as to the underlying mechanism of HIV-induced neuropathogenesis, two complementary concepts predominate. Firstly, HIV-1 encoded proteins injure neurons directly without requiring the intermediary functions of nonneuronal cells. Alternatively, neuronal apoptosis may result indirectly from the secretion of neurotoxic host molecules by resident brain macrophages or microglia in response to HIV-1 infection, stimulation by viral proteins or immune activation. Herein, we review the neurological disorders and their underlying mechanisms associated with HIV infection, focusing on HIV-associated dementia (HAD) and HIV sensory neuropathy (HIV-SN). The evidence that neuronal loss in HIV-1-infected individuals may be due to neuronal apoptosis is then discussed. This review also summarizes the current data supporting both the direct and indirect mechanisms by which neuronal death may occur during infection with HIV-1 or the closely related lentiviruses SIV and FIV. Lastly, strategies are examined for treating or preventing HAD by targeting specific neurotoxic mechanisms.
Jones
Gareth
G
Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.
Power
Christopher
C
D015526:AIDS Dementia Complex / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D015497:HIV-1; D006801:Humans; D009336:Necrosis; D009474:Neurons / Q000473:pathology* / Q000821:virology*; D010523:Peripheral Nervous System Diseases / Q000473:pathology / Q000821:virology*