Jaagsiekte sheep retrovirus (JSRV) is a simple betaretrovirus that causes a contagious lung adenocarcinoma in sheep. One unique feature of JSRV is that its envelope (Env) glycoprotein functions as an active oncogene that induces oncogenic transformation in vitro and in vivo. While oncogenesis by JSRV Env protein has been extensively studied, the entry mechanism of JSRV has not been investigated. In this study, we showed that JSRV entry was specifically inhibited by lysosomotropic agents and bafilomycin Al (BafAl), indicating that JSRV is pH-dependent. Interestingly, oncoretroviral pseudotypes bearing JSRV Env protein were not inactivated by an acidic pH treatment, suggesting that additional factors besides low pH are involved in JSRV entry. Indeed, we found that JSRV entry was also blocked by dominant-negative mutants of dynamin and caveolin, raising the possibility that JSRV may use a dynamin-dependent, caveolae-associated pathway for entry. To determine a possible role of JSRV receptor, hyaluronidase 2 (Hyal2), in JSRV entry, we replaced the glycosylphosphatidyl-inositol (GPI) anchor of Hyal2 with the membrane-spanning domain and cytoplasmic tail of vesicular stomatitis virus G protein (VSV-G). We showed that although the transmembrane version of Hyal2 functioned efficiently as a JSRV receptor, JSRV entry mediated by the mutated Hyal2 was no longer inhibited by lysosomotropic agents and BafAl. Taken together, we conclude that JSRV entry is pH-dependent, but appears to use a non-classical pathway for entry. JSRV may provide an exciting novel model for a better understanding of retrovirus entry.

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Diss. (sammanfattning) Umeå : Umeå universitet, 2009. / Härtill 4 uppsatser. Även tryckt utgåva.