Endosomal/lysosomal retention and degradation of major histocompatibility complex class I molecules is induced by myxoma virus

The highly immunosuppressive leporipoxvirus myxoma, previously was shown to promote the loss of cell surface class I major histocompatibility complex (MHC I) molecules. Here, we show that myxoma virus induces the loss of both cell surface and intracellular post-Golgi, beta(2)-microglobulin-associate d MHC I. Myxoma-induced loss of these MHC I molecules is abrogated by vacuo lar ATPase inhibitors, NH4Cl, and leupeptin. Furthermore, immunofluorescenc e microscopic studies reveal that in myxoma-infected cells, beta(2)-microgl obulin-associated MHC I accumulates in Lamp-1(+) vesicular structures, sugg esting that myxoma virus targets MHC I for degradation in late endosomes an d/or lysosomes. These events are regulated by early gene product or product s because they occur unabated in cells infected with myxoma virus in the pr esence of cytosine arabinoside, an inhibitor of DNA synthesis. Studies with baby green monkey kidney cells transfected with wild-type and tail-less fo rms of a mouse MHC I molecule, H-2L(d), indicate that the MHC I cytoplasmic tail is required for myxoma-induced localization in Lamp-1(+) organelles. Myxoma-induced endocytosis and degradation of MHC I may provide the virus w ith a means of dispensing with cell surface MHC I molecules that were loade d with peptides derived from viral proteins synthesized early in infection. (C) 1999 Academic Press.