Retroviral infections of the nervous system can result in widespread neurological dysfunction without overt infection of nervous system cells. This has been shown in infections with the Human Immunodeficiency Virus (HIV), where in spite of the relative paucity of infected astro- oligodendroglia or neurons there are significant functional abnormalities in around 20% of cases. To explain this apparent paradox, it has been proposed that modest infection of some central nervous system cells leads to widespread dysfunction by the specific interaction of some viral products with brain cells, either neurons or glia. An alternative hypothesis is that viral proteins produced in either macrophages or microglia-cells shown to be infected in the brain of AIDS patients - may interfere with the function of CNS cells. This proposal will look at the interaction of two HIV proteins, gp120 and tat, with cellular components, particularly at the cell surface, in two specific aims.
In aim 1 we will extends experiments that have demonstrated that galactosyl ceramide (GalCer or galactocerebroside), or a closely related molecular plays a significant role in the entry of HIV- 1 into cell lines derived from the human nervous system. In these studies (Harouse et al, 1991; Bhat et al, 1991) we showed that antibodies against GalCer inhibited or decreased infection of two cell lines, U373- MG, derived from glioblastoma, and SK-N-MC, derived from a peripheral neuroblastoma and that gp120 bound GalCer in a specific manner. To extend these findings, we will define the region(s) of gp120 responsible for this interaction using several complementary approaches: (i) inhibition of binding by monospecific or monoclonal anti gp120 antibodies (ii) competition for gp120-GalCer binding with peptides (iii) generation of gp120 mutants and (iv) digestion of gp120 with glycosidases.
In aim 2 we will study abnormalities induced in cultured neurons by the HIV transactivator, tat, to understand the region of tat responsible for inducing these abnormalities and to map the receptor on brain cells.
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