Retroviral envelope glycoproteins: mediators of neuropathology in nervous system development and neurodegeneration in HIV-1 infection

Abstract

Better than 90% of AIDS patients have neuropathology identified at autopsy. HIV-1, the causative organism of AIDS, produces neuronal death as a primary viral effect in many AIDS cases, and it does so even though the virus does not infect neurons. The search for the pathomechanisms by which HIV-1 causes neurologic disease has frequently focused on the possible role of the envelope glycoprotein, gpl20, as a mediator of excitotoxicity. Many animal retroviruses of veterinary importance produce neurologic and immunologic syndromes similar to those manifest by HIV-1. The feline retroviruses, feline immunodeficiency virus and feline leukemia virus, are clinically similar to HIV-1 and HTLV-1 (human T-lymphotrophic virus), respectively. Like gpl20 of HIV-1, the envelope glycoprotein of FeLV produces lymphocytic and neuronal toxicity. In the first study of this dissertation, we hypothesized that retroviral envelope glycoproteins can act on advancing growth cones in the developing nervous system, leading to derangement of neuronal connectivity. We tested this hypothesis by applying an oligopeptide derived from the envelope glycoprotein of FeLV to the growth cones of cultured neurons and observing its effect on morphology and calcium regulation. The oligopeptide produced changes manifested as altered morphology, loss of motility, and increased [Ca2+]i. This suggests a mechanism by which FeLV in particular and retroviruses in general might contribute to abnormal nervous system development in perinatal infections. Seizures are a common sequela of HIV-1 infection of the brain. In the second study in this dissertation we hypothesized that the presence of gpl20 in the hippocampus may produce a pattern of neuronal loss similar to that seen in temporal lobe epilepsy. In this study, we exposed cultured cells of the dentate gyrus (granule cells) and hippocampal gyrus (pyramidal cells) to gpl20 to assess their relative sensitivity to its neurotoxicity. Granule cells were resistant to concentrations of gpl20 which produce significant cell death amongst pyramidal cells. Such a pattern of differential neuronal sensitivity and cell loss may constitute the neuroanatomic basis for expression of seizures in AIDS patients. These studies add to the body of evidence that indicates the envelope glycoproteins are important mediators of neuropathology in retroviral infections of the nervous system.