ROLE OF IMMUNE ACTIVATION AND CYTOKINE EXPRESSION IN HIV-1-ASSOCIATEDNEUROLOGIC DISEASES

Central nervous system (CNS) involvement is common during human immuno deficiency virus type-1 (HIV-1) infection. The neurologic disease of t he CNS most frequently observed during acquired immunodeficiency syndr ome (AIDS) is HIV-l-associated cognitive/motor complex or AIDS dementi a complex (ADC), which is most likely a direct consequence of HIV-1 in fection of the CNS. The peripheral nervous system (PNS) is also affect ed in HIV-1-infected individuals and there are several features of imm une- and cytokine-related pathogenesis in both the CNS and PNS that ar e reviewed. Several lines of evidence demonstrate aspects of immune ac tivation in the CNS and peripheral nervous system (PNS) of HIV-1-infec ted individuals. The relative paucity of HIV-1 expression in contrast to widespread functional and pathologic changes in the CNS and PNS of AIDS patients, and the lack of evidence of productive infection of HIV -1 in neuronal cells in vivo lead to the possibility of indirect or im munopathogenic mechanisms for HIV-l-related neurologic diseases. Propo sed mechanisms of neuronal and glial cell damage are injury of oligode ndrocytes by tumor necrosis factor-alpha (TNF-alpha) released from act ivated macrophage/microglia, calcium-dependent excitoneurotoxicity ind uced by gp120 HIV-1 envelope protein, N-methyl-D-aspartate (NMDA) rece ptor-mediated neurotoxicity by quinolinic acid (a product of activated macrophages), cell injury by HIV-l-specific cytotoxic T cells, and ap optosis of oligodendrocytes or neurons triggered by interaction betwee n cell surface receptors and HIV-1 gp120 protein. Common to those mech anisms is the dependence on cellular activation with expression of pro inflammatory cytokines (TNF-alpha, interleukin-1). Amplification of ac tivation signals through the cytokine network by macrophage/astrocyte/ endothelial cell interactions, and cell-to-cell contact between activa ted macrophages and neural cells by upregulation of adhesion molecules dramatically enhances the toxic effect of macrophage products. Expres sion of immunosuppressive cytokines such as interleukin-4, interleukin -6. and transforming growth factor-beta is also increased in the CNS a nd PNS of HIV-1-infected patients. This may serve as neuroprotective a nd regenerative mechanism against insults to nervous system tissue.