Elucidation of the Tissue Tropism Determinants of Jaagsiekte Sheep Retrovirus and Enzootic Nasal Tumor Virus
Bibliographic record
Abstract
Jaagsiekte Sheep Retrovirus (JSRV) and Enzootic Nasal Tumor Virus (ENTV) cause adenocarcinomas of the lung and nasal tract, respectively, in sheep and goats. Nevertheless, JSRV and ENTV share a high degree of nucleotide (nt) (89%) and amino acid (a.a.) (80%) identity. They also enter cells via the same cell receptor, Hyaluronoglucosaminidase 2 (Hyal2), an enzyme involved in epithelial, endothelial and chondrocytic hyaluronan metabolism. Finally, they transform tissues using their envelope (Env) glycoprotein. JSRV and ENTV genome sequence comparisons reveal two regions of dissimilarity: the U3 of the Long Terminal Repeats (LTRs) (35% nt), and the cytoplasmic tail of the Envelope glycoprotein (50% a.a.). To uncover genomic regions important for tropism, we developed JSRV-ENTV chimeras within a JSRV backbone, containing ENTV’s LTRs, structural proteins and Env. Because JSRV and ENTV lack a reporter gene and have difficulty propagating in vitro, we also employed lentivectors (LV) pseudotyped with the JSRV Env (Jenv) and ENTV Env (Eenv), and developed a tissue slice ex vivo model to study entry of JSRV, ENTV and the chimeras. Our data demonstrated that, unlike JSRV and Jenv LV, ENTV and Eenv LV could not infect or transduce ovine lung tissue slices. Furthermore, JSRV LTRs were statistically significantly less active than ENTV LTRs in primary ovine chondrocyte cells. We also observed strong staining against Env in ENTV-infected ovine nasal turbinate slices, particularly in chondrocytes. Our in vitro data also showed that lentivectors pseudotyped with Eenv best transduced ovine primary chondrocytes, similarly to cells overexpressing Hyal2, revealing new aspects of ENTV pathogenesis. These results suggest that JSRV and ENTV tissue selectivity requires both Env and the LTRs. This marked tissue specificity allowed us to explore Jenv as an LV pseudotype in lung gene therapy. We generated two novel Jenv mutants to pseudotype LV, yielding titers similar to Vesicular Stomatitis Virus glycoprotein pseudotyped LV, capable of efficiently transducing both ovine and Hyal2-expressing murine lung slices. Overall, this thesis proposes that JSRV and ENTV tropism is orchestrated by both their promoters and Env glycoproteins, and that their tissue specificity can be re-purposed for gene therapy to the lung.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".