Role of immune activation and cytokine expression in HIV-1-associated neurologic diseases.
Central nervous system (CNS) involvement is common during human immunodeficiency virus type-1 (HIV-1) infection. The neurologic disease of the CNS most frequently observed during acquired immunodeficiency syndrome (AIDS) is HIV-1-associated cognitive/motor complex or AIDS dementia complex (ADC), which is most likely a direct consequence of HIV-1 infection of the CNS. The peripheral nervous system (PNS) is also affected in HIV-1-infected individuals and there are several features of immune- and cytokine-related pathogenesis in both the CNS and PNS that are reviewed. Several lines of evidence demonstrate aspects of immune activation in the CNS and peripheral nervous system (PNS) of HIV-1-infected 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 immunopathogenic mechanisms for HIV-1-related neurologic diseases. Proposed mechanisms of neuronal and glial cell damage are injury of oligodendrocytes by tumor necrosis factor-alpha (TNF-alpha) released from activated macrophage/microglia, calcium-dependent excitoneurotoxicity induced by gp120 HIV-1 envelope protein, N-methyl-D-aspartate (NMDA) receptor-mediated neurotoxicity by quinolinic acid (a product of activated macrophages), cell injury by HIV-1-specific cytotoxic T cells, and apoptosis of oligodendrocytes or neurons triggered by interaction between cell surface receptors and HIV-1 gp120 protein. Common to those mechanisms is the dependence on cellular activation with expression of proinflammatory cytokines (TNF-alpha, interleukin-1). Amplification of activation signals through the cytokine network by macrophage/astrocyte/endothelial cell interactions, and cell-to-cell contact between activated macrophages and neural cells by upregulation of adhesion molecules dramatically enhances the toxic effect of macrophage products. Expression of immunosuppressive cytokines such as interleukin-4, interleukin-6, and transforming growth factor-beta is also increased in the CNS and PNS of HIV-1-infected patients. This may serve as neuroprotective and regenerative mechanism against insults to nervous system tissue.
Yoshioka
M
M
Department of Neurology, Tohoku University School of Medicine, Sendai, Japan.
Bradley
W G
WG
Shapshak
P
P
Nagano
I
I
Stewart
R V
RV
Xin
K Q
KQ
Srivastava
A K
AK
Nakamura
S
S
D015526:AIDS Dementia Complex / Q000276:immunology* / Q000473:pathology / Q000628:therapy / Q000821:virology; D017209:Apoptosis; D002448:Cell Adhesion; D016207:Cytokines / Q000145:classification / Q000502:physiology*; D004730:Endothelium, Vascular / Q000473:pathology; D018698:Glutamic Acid / Q000502:physiology; D015699:HIV Envelope Protein gp120 / Q000502:physiology; D015658:HIV Infections / Q000150:complications / Q000276:immunology; D015497:HIV-1 / Q000276:immunology / Q000502:physiology*; D006801:Humans; D016131:Lymphocyte Subsets / Q000276:immunology / Q000821:virology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology / Q000821:virology; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology / Q000821:virology; D009474:Neurons / Q000473:pathology / Q000821:virology; D009569:Nitric Oxide / Q000502:physiology; D010523:Peripheral Nervous System Diseases / Q000209:etiology / Q000276:immunology; D017378:Quinolinic Acid / Q000378:metabolism; D017470:Receptors, Glutamate / Q000502:physiology
D016207:Cytokines; D015699:HIV Envelope Protein gp120; D017470:Receptors, Glutamate; D009569:Nitric Oxide; D018698:Glutamic Acid; D017378:Quinolinic Acid