Retroviruses in foreign species and the problem of provirus silencing

Retroviruses are known to integrate in the host cell genome as proviruses, and therefore they are prone to cell-mediated control at the transcriptional and posttranscriptional levels. This plays an important role especially after retrovirus heterotransmission to foreign species, but also to differentiated cells. In addition to host cell-mediated blocks in provirus expression, also so far undefined host specificities, deciding upon the pathogenic manifestation of retrovirus heterotransmission, are in play. In this respect, we discuss especially the occurrence of wasting disease and immunodeficiency syndrome, which we established also in avian species using avian leukosis virus subgroup C (ALV-C) inoculated in mid-embryogenesis in duck or chicken embryos. The problem of provirus downregulation in foreign species or in differentiated cells has been in the recent years approached experimentally. From a series of observations it became apparent that provirus downregulation is mediated by its methylation, especially in the region of proviral enhancer-promoter located in long terminal repeats (LTR). Several strategies have been devised in order to protect the provirus from methylation using LTR modification and/or introducing in the LTR sequence motifs acting as antimethylation tags. In such a way the expression of retroviruses and vectors in foreign species, as well as in differentiated cells, has been significantly improved. The complexity of the mechanisms involved in provirus downregulation and further possibilities to modulate it are discussed.