1887

Abstract

In spite of an eradication campaign that eliminated clinical cases of caprine arthritis encephalitis virus-induced arthritis in the Swiss goat population, seroconversions are still observed. In the affected flocks, viruses belonging mainly to the small ruminant lentivirus A4 subtype are regularly isolated. These viruses are considered attenuated, except in the mammary gland, where high viral loads and histopathological lesions have been observed. We previously characterized and sequenced such field isolates, detecting several potentially attenuating mutations in their LTR. Here we present a detailed analysis of the promoter activity of these genetic elements, which was comparable to those of virulent isolates. An AP-1 binding site was shown to be crucial for promoter activity in reporter gene assays and also in the context of a replicating molecular clone. Other sites, such as AML(vis) and a conserved E-box, appeared to be less crucial. Analysis of a unique AP-4 site showed a clear discrepancy between results obtained with reporter gene assays and those with mutated viruses. Within the limits of this study, we did not find evidence pointing to the LTR as the genetic correlate of attenuation for these viruses. Finally, the limited replication of SRLV A4 in mammary cell culture could not explain the suggested mammary tropism. In contrast, and in view of the abundance of macrophages in the mammary gland, it is the striking replication capacity of SRLV A4 in these cells, unaffected by all LTR mutations tested, which may explain the apparent mammary tropism of these viruses.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.000489
2016-07-01
2020-01-24
Loading full text...

Full text loading...

/deliver/fulltext/jgv/97/7/1699.html?itemId=/content/journal/jgv/10.1099/jgv.0.000489&mimeType=html&fmt=ahah

References

  1. Agnarsdóttir G., Thorsteinsdóttir H., Oskarsson T., Matthíasdóttir S., Haflidadóttir B. S., Andrésson O. S., Andrésdóttir V.. 2000; The long terminal repeat is a determinant of cell tropism of maedi-visna virus. J Gen Virol81:1901–1905 [CrossRef][PubMed]
    [Google Scholar]
  2. Andrésdóttir V., Tang X., Andrésson O. S., Georgsson G.. 1994; Sequence variation in the envelope gene and the LTR of maedi-visna virus. Ann N Y Acad Sci724:157–158[PubMed][CrossRef]
    [Google Scholar]
  3. Angelopoulou K., Brellou G. D., Greenland T., Vlemmas I.. 2006; A novel deletion in the LTR region of a Greek small ruminant lentivirus may be associated with low pathogenicity. Virus Res118:178–184 [CrossRef][PubMed]
    [Google Scholar]
  4. Angelopoulou K., Poutahidis T., Brellou G. D., Greenland T., Vlemmas I.. 2008; A deletion in the R region of long terminal repeats in small ruminant lentiviruses is associated with decreased pathology in the lung. Vet J175:346–355 [CrossRef][PubMed]
    [Google Scholar]
  5. Barros S. C., Andrésdóttir V., Fevereiro M.. 2005; Cellular specificity and replication rate of Maedi Visna virus in vitro can be controlled by LTR sequences. Arch Virol150:201–213 [CrossRef][PubMed]
    [Google Scholar]
  6. Bertoni G., Blacklaws B.. 2010; Small ruminant lentiviruses and cross-species transmission. In Lentiviruses and Macrophages: Molecular and Cellular Interactions pp277–306 Edited by Desport M.. Norfolk, UK: Caister Academic Press;
    [Google Scholar]
  7. Bertoni G., Blatti-Cardinaux L.. 2016; Small Ruminant Lentivirus Infections in Goats. In Recent Adavances in Goat Diseases . Edited by Tempesta M.. Ithaca NY, USA: International Veterinary Information Service;
    [Google Scholar]
  8. Blacklaws B. A.. 2012; Small ruminant lentiviruses: immunopathogenesis of visna-maedi and caprine arthritis and encephalitis virus. Comp Immunol Microbiol Infect Dis35:259–269 [CrossRef][PubMed]
    [Google Scholar]
  9. Blacklaws B. A., Berriatua E., Torsteinsdottir S., Watt N. J., de Andres D., Klein D., Harkiss G. D.. 2004; Transmission of small ruminant lentiviruses. Vet Microbiol101:199–208 [CrossRef][PubMed]
    [Google Scholar]
  10. Blatti-Cardinaux L., Pisoni G., Stoffel M. H., Zanoni R., Zahno M. L., Bertoni G.. 2016; Generation of a molecular clone of an attenuated lentivirus, a first step in understanding cytopathogenicity and virulence. Virology487:50–58 [CrossRef][PubMed]
    [Google Scholar]
  11. Campbell B. J., Avery R. J.. 1996; Sequence analysis and transcriptional activity of the LTR of OLV-CU1, a North American ovine lentivirus. J Gen Virol77:2999–3004 [CrossRef][PubMed]
    [Google Scholar]
  12. Cardinaux L., Zahno M. L., Deubelbeiss M., Zanoni R., Vogt H. R., Bertoni G.. 2013; Virological and phylogenetic characterization of attenuated small ruminant lentivirus isolates eluding efficient serological detection. Vet Microbiol162:572–581 [CrossRef][PubMed]
    [Google Scholar]
  13. Chebloune Y., Sheffer D., Karr B. M., Stephens E., Narayan O.. 1996; Restrictive type of replication of ovine/caprine lentiviruses in ovine fibroblast cell cultures. Virology222:21–30 [CrossRef][PubMed]
    [Google Scholar]
  14. Da Silva Teixeira M. F., Lambert V., Mselli-Lakahl L., Chettab A., Chebloune Y., Mornex J. F.. 1997; Immortalization of caprine fibroblasts permissive for replication of small ruminant lentiviruses. Am J Vet Res58:579–584[PubMed]
    [Google Scholar]
  15. Deubelbeiss M., Blatti-Cardinaux L., Zahno M. L., Zanoni R., Vogt H. R., Posthaus H., Bertoni G.. 2014; Characterization of small ruminant lentivirus A4 subtype isolates and assessment of their pathogenic potential in naturally infected goats. Virol J11:65–75 [CrossRef][PubMed]
    [Google Scholar]
  16. Duverger A., Wolschendorf F., Zhang M., Wagner F., Hatcher B., Jones J., Cron R. Q., van der Sluis R. M., Jeeninga R. E.. 2013; An AP-1 binding site in the enhancer/core element of the HIV-1 promoter controls the ability of HIV-1 to establish latent infection. J Virol87:2264–2277 [CrossRef][PubMed]
    [Google Scholar]
  17. Gabuzda D. H., Hess J. L., Small J. A., Clements J. E.. 1989; Regulation of the visna virus long terminal repeat in macrophages involves cellular factors that bind sequences containing AP-1 sites. Mol Cell Biol9:2728–2733[PubMed][CrossRef]
    [Google Scholar]
  18. Glaria I., Reina R., Ramírez H., de Andrés X., Crespo H., Jauregui P., Salazar E., Luján L., Pérez M. M. et al. 2012; Visna/Maedi virus genetic characterization and serological diagnosis of infection in sheep from a neurological outbreak. Vet Microbiol155:137–146 [CrossRef][PubMed]
    [Google Scholar]
  19. Grego E., Bertolotti L., Quasso A., Profiti M., Lacerenza D., Muz D., Rosati S.. 2007; Genetic characterization of small ruminant lentivirus in Italian mixed flocks: evidence for a novel genotype circulating in a local goat population. J Gen Virol88:3423–3427 [CrossRef][PubMed]
    [Google Scholar]
  20. Harmache A., Bouyac M., Audoly G., Hieblot C., Peveri P., Vigne R., Suzan M.. 1995a; The vif gene is essential for efficient replication of caprine arthritis encephalitis virus in goat synovial membrane cells and affects the late steps of the virus replication cycle. J Virol69:3247–3257
    [Google Scholar]
  21. Harmache A., Russo P., Guiguen F., Vitu C., Vignoni M., Bouyac M., Hieblot C., Pepin M., Vigne R., Suzan M.. 1996a; Requirement of caprine arthritis encephalitis virus vif gene for in Vivo replication. Virology224:246–255[CrossRef]
    [Google Scholar]
  22. Harmache A., Russo P., Vitu C., Guiguen F., Mornex J.-F., Pepin, M., VigneI R., Suzan M.. 1996b; Replication in goats in vivo of caprine arthritis–encephalitis Virus deleted in vif or tat genes: possible use of these deletion mutants as live Vaccines. AIDS Res Hum Retro viruses12:409–411[CrossRef]
    [Google Scholar]
  23. Harmache A., Vitu C., Russo P., Bouyac M., Hieblot C., Peveri P., Vigne R., Suzan M.. 1995b; The caprine arthritis encephalitis virus tat gene is dispensable for efficient viral replication in vitro and in vivo. J Virol69:5445–5454
    [Google Scholar]
  24. Heaton M. P., Clawson M. L., Chitko-Mckown C. G., Leymaster K. A., Smith T. P., Harhay G. P., White S. N., Herrmann-Hoesing L. M., Mousel M. R.. 2012; Reduced lentivirus susceptibility in sheep with TMEM154 mutations. PLoS Genet8:e1002467 [CrossRef][PubMed]
    [Google Scholar]
  25. Hess J. L., Pyper J. M., Clements J. E.. 1986; Nucleotide sequence and transcriptional activity of the caprine arthritis-encephalitis virus long terminal repeat. J Virol60:385–393[PubMed]
    [Google Scholar]
  26. Hess J. L., Small J. A., Clements J. E.. 1989; Sequences in the visna virus long terminal repeat that control transcriptional activity and respond to viral trans-activation: involvement of AP-1 sites in basal activity and trans-activation. J Virol63:3001–3015[PubMed]
    [Google Scholar]
  27. Juganaru M., Reina R., Grego E., Profiti M., Rosati S.. 2010; LTR promoter activity of SRLV genotype E, strain Roccaverano. Vet Res Commun34:Suppl 1S47–S51 [CrossRef][PubMed]
    [Google Scholar]
  28. Kristbjörnsdóttir H. B., Andrésdóttir V., Svansson V., Torsteinsdóttir S., Matthíasdóttir S., Andrésson O. S.. 2004; The vif gene of maedi-visna virus is essential for infectivity in vivo and in vitro. Virology318:350–359 [CrossRef][PubMed]
    [Google Scholar]
  29. Minardi da Cruz J. C., Singh D. K., Lamara A., Chebloune Y.. 2013; Small ruminant lentiviruses (SRLVs) break the species barrier to acquire new host range. Viruses5:1867–1884 [CrossRef][PubMed]
    [Google Scholar]
  30. Murphy B., Hillman C., Castillo D., Vapniarsky N., Rowe J.. 2012; The presence or absence of the gamma-activated site determines IFN gamma-mediated transcriptional activation in CAEV promoters cloned from the mammary gland and joint synovium of a single CAEV-infected goat. Virus Res163:537–545 [CrossRef][PubMed]
    [Google Scholar]
  31. Murphy B., McElliott V., Vapniarsky N., Oliver A., Rowe J.. 2010; Tissue tropism and promoter sequence variation in caprine arthritis encephalitis virus infected goats. Virus Res151:177–184 [CrossRef][PubMed]
    [Google Scholar]
  32. Narayan O., Wolinsky J. S., Clements J. E., Strandberg J. D., Griffin D. E., Cork L. C.. 1982; Slow virus replication: the role of macrophages in the persistence and expression of visna viruses of sheep and goats. J Gen Virol59:345–356 [CrossRef][PubMed]
    [Google Scholar]
  33. Oskarsson T., Hreggvidsdóttir H. S., Agnarsdóttir G., Matthíasdóttir S., Ogmundsdóttir M. H., Jónsson S. R., Georgsson G., Ingvarsson S., Andrésson O. S. et al. 2007; Duplicated sequence motif in the long terminal repeat of maedi-visna virus extends cell tropism and is associated with neurovirulence. J Virol81:4052–4057 [CrossRef][PubMed]
    [Google Scholar]
  34. Pyra H., Böni J., Schüpbach J.. 1994; Ultrasensitive retrovirus detection by a reverse transcriptase assay based on product enhancement. Proc Natl Acad Sci U S A91:1544–1548[PubMed][CrossRef]
    [Google Scholar]
  35. Ramírez H., Reina R., Amorena B., de Andrés D., Martínez H. A.. 2013; Small ruminant lentiviruses: genetic variability, tropism and diagnosis. Viruses5:1175–1207 [CrossRef][PubMed]
    [Google Scholar]
  36. Reina R., Grego E., Bertolotti L., De Meneghi D., Rosati S.. 2009; Genome analysis of small-ruminant lentivirus genotype E: a caprine lentivirus with natural deletions of the dUTPase subunit, vpr-like accessory gene, and 70-base-pair repeat of the U3 region. J Virol83:1152–1155 [CrossRef][PubMed]
    [Google Scholar]
  37. Ryan S., Tiley L., McConnell I., Blacklaws B.. 2000; Infection of dendritic cells by the Maedi-Visna lentivirus. J Virol74:10096–10103[PubMed][CrossRef]
    [Google Scholar]
  38. Shah C., Böni J., Huder J. B., Vogt H. R., Mühlherr J., Zanoni R., Miserez R., Lutz H., Schüpbach J.. 2004; Phylogenetic analysis and reclassification of caprine and ovine lentiviruses based on 104 new isolates: evidence for regular sheep-to-goat transmission and worldwide propagation through livestock trade. Virology319:12–26 [CrossRef][PubMed]
    [Google Scholar]
  39. Sokal R. R., Rohlf F. J.. 1995; Biometry: The Principles and Practice of Statistics in Biological Research New York: W.H. Freeman and Company;
    [Google Scholar]
  40. Sutton K. A., Lin C. T., Harkiss G. D., McConnell I., Sargan D. R.. 1997; Regulation of the long terminal repeat in visna virus by a transcription factor related to the AML/PEBP2/CBF superfamily. Virology229:240–250 [CrossRef][PubMed]
    [Google Scholar]
  41. Tong-Starksen S. E., Sepp T., Pagtakhan A. S.. 1996; Activation of caprine arthritis-encephalitis virus long terminal repeat by gamma interferon. J Virol70:595–599[PubMed]
    [Google Scholar]
  42. Turelli P., Guiguen F., Mornex J. F., Vigne R., Quérat G.. 1997; dUTPase-minus caprine arthritis-encephalitis virus is attenuated for pathogenesis and accumulates G-to-A substitutions. J Virol71:4522–4530[PubMed]
    [Google Scholar]
  43. Turelli P., Pétursson G., Guiguen F., Mornex J. F., Vigne R., Quérat G.. 1996; Replication properties of dUTPase-deficient mutants of caprine and ovine lentiviruses. J Virol70:1213–1217[PubMed]
    [Google Scholar]
  44. White S. N., Knowles D. P.. 2013; Expanding possibilities for intervention against small ruminant lentiviruses through genetic marker-assisted selective breeding. Viruses5:1466–1499 [CrossRef][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.000489
Loading
/content/journal/jgv/10.1099/jgv.0.000489
Loading

Data & Media loading...

Supplements

Supplementary File 1

PDF

Most cited articles

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error