AIDS-DEMENTIA DUE TO GP120 HOMOLOGY TO NEUROLEUKIN

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Neuroleukin is a polypeptide factor which exhibits both neurotrophic and lymphokine activities. A region of the GP120 external envelope protein of HIV is partially homologous to neuroleukin. The homology is to a segment of the ENV gene which is conserved in all HIV isolates for which sequence information has been reported. Recombinant neuroleukin supports the continued survival in culture of spinal and sensory neurons. Message encoding neuroleukin is expressed in brain and we hypothesize that neuroleukin is important for the growth and function of neurons within the CNS. Neuroleukin is also a lymphokine. It is a lectin-stimulated T-cell product and acts to induce immunoglobulin synthesis by cultured human peripheral blood mononuclear cells. We hypothesize that the sequence homology of GP120 to neuroleukin contributes to the subacute encephalitis and to the polyclonal B-cell activation seen in AIDs. Our initial experiments indicate that the GP120 protein has neuroleukin-agonist/antagonist activity and that the activity resides in the neuroleukin-homology segment. To extend our work, we propose to determine if fragments of GP120 which contain the neuroleukin homology segment are encephalitic in animals. We also will show that the pathological effects of GP120 fragments are due to a neuroleukin-dependent mechanism, and that that mechanism involves agonist/antagonist interaction with the neuroleukin receptor on neurons. The project could lead to development of a therapeutic agent and/or a peptide vaccine against HIV.