Cytokine dysregulation in HIV-associated neurological disease

AIDS is associated with three major neurological syndromes: dementia (HIVD), vacuolar myelopathy (VM) and plainful sensory neuropathy (PSN). The pathogenesis of these conditions remains unclear although they all demonstrate a marked increase in macrophage number and activation despite systemic immunosuppression. It was therefore of interest to determine the profile of cytokine and HIV expression in brain, spinal cord and peripheral nerves of AIDS patients with AD, VM and PSN, as compared to AIDS patients without neurological disease and seronegative controls. RNA was extracted from brain, spinal cord and peripheral nerve and RT/PCR for cytokine and HIV mRNA was performed. In situ RT/PCR was performed to determine the number and type of cells expressing cytokine message and this was compared o the number of cells containing HIV DNA detected with in situ PCR. We found a consistent profile of increased TNFα and decreased IFNγ and IL4 in all three syndromes compared to AIDS patients without neurological disease. IL1 did not increase in parallel with TNFα IL10 was decreased in the VM tissue. HIV transcripts were increased in the AD brains compared to non-demented controls but were detected only occasionally in spinal cord and not at all in peripheral nerve. Preliminary data from in situ RT/PCR suggests that a large number of cells are expressing. TNFα but only a small number are infected with HIV. The finding of elevated TNFα associated with increased macrophage activation and decreased IL4 suggests that the loss of a subset of T cells expressing macrophage regulatory lymphokines such as IL4 and IL10 may explain the observed macrophage activation seen in the neurological diseases associated with AIDS and play a role in the development of neuronal dysfunction.