HUMAN CELL-RECEPTOR CD46 IS DOWN-REGULATED THROUGH RECOGNITION OF A MEMBRANE-PROXIMAL REGION OF THE CYTOPLASMIC DOMAIN IN PERSISTENT MEASLES-VIRUS INFECTION

Monkey cells persistently infected by measles virus (MV) Biken strain (Biken-CV-1 cells) showed no cytopathic effects and lacked surface exp ression of a homolog of human cell receptor, membrane cofactor protein CD46. Transfection of a human CD46 gene into these cells induced exte nsive cell fusion, indicating that down regulation of the endogenous C D46 homolog was essential for the maintenance of a noncytopathic mode of infection. Surface expression of the exogenously introduced human C D46 was also drastically down regulated in the persistently infected c ells compared with uninfected cells, The down regulation was specific for CD46 and did not affect surface expression of exogenously introduc ed CD4. Exogenous human CD46 was synthesized efficiently in the persis tently infected cells, but it did not accumulate on the cell surface. Fusion of Biken-CV-1 cells required the extracellular hemagglutinin (H -protein)-binding domain but not the cytoplasmic domain. Replacing the transmembrane and cytoplasmic domains of CD46 with a glycosylphosphat idylinositol anchor did not prevent cell fusion but completely allevia ted down regulation of the glyco glyphosphatidylinositol-anchored CD46 in Biken-CV-1 cells. Deletion analyses revealed that the membrane-dis tal sequences of the CD46 cytoplasmic domain were not only unnecessary but also inhibitory for CD46 down regulation. By contrast, the six am ino acid residues proximal to the membrane contained a sequence requir ed for CD46 down regulation in the persistently infected cells. These results indicate that CD46 is down regulated in the persistently infec ted cells by a mechanism that recognizes a membrane-proximal sequence in the CD46 cytoplasmic domain.