Neurophysiological changes following simian immunodeficiency virus infection: A model for neuro-AIDS
Human immunodeficiency virus (HIV-1) infects the central nervous system (CNS) early in the course of disease progression and about 20% of HIV+ patients later develop neurological signs that include impaired cognitive ability and psychomotor slowing. Both symptomatic and asymptomatic, HIV-infected subjects show abnormalities in neurophysiology. As part of an effort to establish an animal model of neuroAIDS, we recorded multimodal sensory and motor evoked potentials (EPs) from a total of nine behaviorally trained rhesus macaques infected with passaged strains of the simian immunodeficiency virus SIV mac (R71/E17). Previous work using bone marrow passaged strains of SIV mac R71 and 17E have shown that these macrophage tropic strains of the viruses enter the rhesus macaque brain early following inoculation though the extent of neurological impairment was unknown.
In these studies, the animals were inoculated at two different time points six months apart allowing four of the animals to serve initially as controls. Seven of nine monkeys developed simian AIDS within four months of inoculation and were euthanized (the fast progressors). Two animals remained free of AIDS-related illness for over 18 months following inoculation (the slow progressors). The slow progressors eventually were euthanized due to systemic complications that included disseminated tumors and acute liver dysfunction. The rapid progressors exhibited the most significant changes in all the evoked potential types tested that included: auditory brainstem responses, flash visual evoked potentials, somatosensory potentials stimulated from both the fore and hindlimb and spinal and transcranial motor evoked potentials. From control data gathered over a period of six months, comparisons were made between pre-inoculation and post-inoculation data within subjects as well as across groups. Using the control data for comparison, the animals with slowly progressing disease showed no significant changes in any evoked potentials type tested. The rapid progressors, in contrast, exhibited increases in the latency as well as decreases in the amplitude of the response. In cases a complete loss of the evoked potential occurred. Upon histological examination, the rapid progressors exhibited classic signs of SIV induced neuropathology; the degree of neuropathology often related to the severity of changes observed in neurophysiology. Histologically, the slow progressors exhibited no remarkable pathology. In conclusion, the SIV mac R71/17E model recapitulates many of the hallmark conditions of HIV-1 disease. Instead of taking years to develop end-stage disease like HIV, the SIVmac R71/17E model developed end-stage disease within 14 weeks and allowed for greater control of possibly confounding variables such route and time of infection and possible use of more invasive techniques for investigation. Using multi-modal evoked potentials, we have shown that significant neurophysiological changes occur following SIVmac R71/17E infection. The most severe neurophysiological changes were recorded from animals with rapidly progressing disease. Our model, subsequently, may prove useful in the development of antiviral pharmaceuticals, exploring the mechanisms of patho-neurophysiology as well as the interaction between retroviruses and drugs of addiction.