INTRACELLULAR DIVERSION OF GLYCOPROTEIN-GP160 OF HUMAN-IMMUNODEFICIENCY-VIRUS TO LYSOSOMES AS A STRATEGY OF AIDS GENE-THERAPY

A potential gene therapy strategy against human immunodeficiency virus (HIV-1) is to disrupt the intracellular transport of viral proteins. We report here the binding and transporting of HIV-1 glycoprotein gp16 0 to lysosomes as a result of the expression of fusion genes consistin g of soluble CD4 and lysosome targeting domains. The effective lysosom e targeting domain tested includes a lysosomal protease zymogen, proca thepsin D, and the COOH-terminal domains of three lysosome membrane pr oteins: lamp-1, lamp-2, and lysosomal acid phosphatase. We demonstrate d that cell fusion (syncytium), caused by the transport of gp160 to th e surface of HeLa-CD4+ cells, was completely abolished by the expressi on of these fusion genes. The lysosomal localization of gp160 in HeLa cells coexpressing CD4-fusion genes was also established. From pulse-c hase experiments, we observed that gp160 and the fusion proteins were degraded, as expected of lysosomal activities. Additionally, T lymphob lastoid cells transiently and permanently expressing these fusion gene s strongly retarded the propagation of human immunodeficiency virus ty pe 1. Thus, these fusion genes can deprive HIV of newly synthesized en velope protein gp160 for the assembly of new virions and are potential ly useful in gene therapy against AIDS.