Inmunología en el complejo de demencia asociado con el SIDA
Cytokines, Chemokines and HIV-Associated Dementia
María José Míguez, MD, Ph.D., Universidad de Miami, EE.UU.
Over the past two decades, there has been a dramatic increase in our understanding of neuropathogenesis. The neurodegenerative process was once thought to result from opportunistic infections, and then from HIV itself. Because the low number of infected cells in the brain cannot explain the extent of damage observed in HIV-1 associated dementia (HAD), it is now widely accepted that viral proteins shed by infected cells, as well as a variety of toxic products secreted by activated cells (cytokines, chemokines), are the major factors involved in HIV/AIDS neuropathology.
The pathogenesis of HAD remains unclear, but is thought to originate with entry of HIV into the CNS, either by direct infection of capillary endothelial cells or more likely by entrance of infected macrophages. Following entry into the brain, activated HIV-infected macrophages and astrocytes release cytokines, reactive oxygen species, and several neurotoxins that impair cellular functioning, modify neurotransmitter action, and may be the basis for leukoencephalopathy and neuronal loss. Proinflammatory cytokines are major mediators of neurotoxic reactions in HIV associated dementia and are known to parallel neurocognitive dysfunction. Increased levels of pro-inflammatory cytokines such as IL-1, IFN-, TGF, TNF-, and IL-6, can produce prostaglandins, iNOS, enhance HIV-1 replication through increased NFB transcription factor and can inhibit the ability of astrocytes to buffer extracellular glutamate thus, causing apoptosis. Cytokines such as TNF- and IL-1 in the brain can adversely affect oligodendrocyte function and pituitary hormone secretion, as well as induce fever, nausea and loss of appetite, explaining some of the more general symptoms associated with HIV-1-associated dementia.
Chemokines are a family of small cytokines typically produced by damaged or infected cells, which function mainly as chemoattractants. In HIV-1 encephalopathy, it is likely that chemokines contribute to pathogenesis by: 1) acting as co-receptors facilitating HIV entry into the brain, 2) bringing increased numbers of infected and/or activated monocytes into the brain, and 3) by direct action on neurons to induce death. Some chemokines, (i.e. MIP-1, RANTES, Fractalkine), however can also prevent gp120-induced neuronal death, or protect neurons from the toxic effects of HIV-1-Tat protein and platelet activating factor.
The limited availability of HAART treatment worldwide, along with its limited access across the blood-brain-barrier and potential resistance, underscore the importance of determining neuroimmune responses that could form the basis for therapeutic options to reduce HIV neurodegeneration.