Abstract
Jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV) are small-ruminant betaretroviruses that share high nucleotide and amino acid identity, utilize the same cellular receptor, hyaluronoglucosaminidase 2 (Hyal2) for entry, and transform tissues with their envelope (Env) glycoprotein; yet, they target discrete regions of the respiratory tract—the lung and nose, respectively. This distinct tissue selectivity makes them ideal tools with which to study the pathogenesis of betaretroviruses. To uncover the genetic determinants of tropism, we constructed JSRV–ENTV chimeric viruses and produced lentivectors pseudotyped with the Env proteins from JSRV (Jenv) and ENTV (Eenv). Through the transduction and infection of lung and nasal turbinate tissue slices, we observed that Hyal2 expression levels strongly influence ENTV entry, but that the long terminal repeat (LTR) promoters of these viruses are likely responsible for tissue-specificity. Furthermore, we show evidence of ENTV Env expression in chondrocytes within ENTV-infected nasal turbinate tissue, where Hyal2 is highly expressed. Our work suggests that the unique tissue tropism of JSRV and ENTV stems from the combined effort of the envelope glycoprotein-receptor interactions and the LTR and provides new insight into the pathogenesis of ENTV.
Highlights
Jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV) are two small-ruminant betaretroviruses that infect sheep, causing ovine pulmonary adenocarcinoma (OPA) and enzootic nasal adenocarcinoma (ENA), respectively [1,2]
Using chimeric viruses and lentivectors pseudotyped with Eenv and Jenv in ex vivo ovine lung and nasal turbinate tissue slice models, we found that JSRV and ENTV tissue tropism is orchestrated by the combined effort of the envelope and
We observed a slight difference in molecular weight between Eenv and Jenv in the western blots of lysates from cells transfected with JSRV, chimeras encoding Jenv (Chm1-ERU3, Chm2-Egag, Chm4-EU3, and Chm5-ELTR) and ENTV, and a chimera encoding Eenv (Chm3-Eenv); and in the viral lysates from these samples
Summary
Jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV) are two small-ruminant betaretroviruses that infect sheep, causing ovine pulmonary adenocarcinoma (OPA) and enzootic nasal adenocarcinoma (ENA), respectively [1,2]. JSRV and ENTV share high nucleotide and amino acid identity and utilize the same cellular receptor, hyaluronoglucosaminidase-2 (Hyal2), for entry [3,4]. Their envelope (Env) glycoprotein functions as a potent oncogene, which is rare amongst retroviruses [5,6,7]. Despite these similarities, JSRV and ENTV cause disease in different anatomical locations of the respiratory tract. JSRV pathogenesis depends on the availability of Viruses 2019, 11, 1061; doi:10.3390/v11111061 www.mdpi.com/journal/viruses
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