This project studies biochemical and immunological aspects of myelin disorders in neuro-AIDS. Myelin-associated glycoprotein (MAG) and -CD4 both belong to the immunoglobulin gene superfamily. Its members generally serve in recognition processes, and human CD4 is also the receptor for gp120 of HIV. There is some homology between the binding site of CD4 for gp120 and MAG. Soluble dMAG (a proteolytic cleavage product of MAG containing all five extracellular domains) was chemically purified with the intent to grow native dMAG crystals and to determine their structure by X-ray diffraction. Postmortem subcortical white matter samples from AIDS patients with and without dementia were analyzed for quantitative and qualitative alterations of myelin proteins, including MAG, myelin basic protein, proteolipid protein and 2', 3'-cyclic nucleotide 3'- phosphodiesterase. Diffuse myelin pallor (DMP) was detected histologically (indicated by a decreased staining with luxol fast blue) in about one-half of demented patients and one-fourth of the nondemented patients. The biochemical results were correlated with histological and immunocytochemical observations made by our collaborators at Johns Hopkins University on adjacent tissue sections. However, electron microscopic, immunocytochemical and biochemical analyses of white matter indicated little or no loss of myelin proteins in areas of prominent DMP. The same was found when demented and nondemented AIDS patients samples were compared to controls. Astrocytic hypertrophy was found in some of the AIDS patients both histologically and by increased levels of glial fibrillary acidic protein detected biochemically. Significant accumulation of serum proteins was detected immunocytochemically in white matter of many of the AIDS cases, especially the demented ones. This was supported biochemically by the presence of variable levels of haptoglobin on western blots of AIDS samples but not of control samples. Overall, the results provide little evidence for significant demyelination or myelin pathology in subcortical white matter of AIDS brain, but suggest that blood brain barrier perturbation may contribute to CNS pathology in AIDS and AIDS dementia. Also, substantial conversion of MAG to dMAG was observed in some AIDS samples, as had previously been found in many samples from multiple sclerosis brains (Z01NS02848-04LMCN). The relationship of blood brain barrier breakdown to the proteolytic MAG/dMAG conversion observed in multiple sclerosis and the AIDS brain is under investigation.
