Elsevier

Virus Research

Volume 151, Issue 2, August 2010, Pages 177-184
Virus Research

Tissue tropism and promoter sequence variation in caprine arthritis encephalitis virus infected goats

https://doi.org/10.1016/j.virusres.2010.05.002Get rights and content

Abstract

Caprine arthritis encephalitis virus is a lentivirus that infects goats and is closely related to maedi-visna virus of sheep. Infection with CAEV results in multiple discrete disease manifestations in goats which can include chronic arthritis, mastitis, pneumonia or encephalomyelitis. Presently, no satisfactory mechanistic rationale for viral tropism has been put forward. We propose that specific sequences in the lentiviral promoter (U3 region of the viral long terminal repeat) are associated with viral tissue tropism and subsequent disease expression. A total of 41 distinct CAE viral promoter regions were amplified, sequenced and phylogenetically compared from the tissues of 24 CAEV-infected goats demonstrating a variety of disease manifestations. Phylogenetically, we identified no tendency for clustering of these promoter sequences into tissue-specific groups. These results therefore do not provide evidence for the study hypothesis. However, multiple motifs within the U3 promoter region were highly conserved both within the entire collection of sequences and within tissue-specific groups.

Introduction

Caprine arthritis encephalitis virus (CAEV) is a pathogenic lentivirus in the family Retroviridae that infects goats and is closely related to the maedi-visna virus (MVV) of sheep (Benavides et al., 2009, Fields et al., 2001). CAEV and MVV are both classified as small ruminant lentiviruses (SRLV) which cause progressive and debilitating illnesses (Maxie and Jubb, 2007). CAEV infection in goats results in four chronic disease syndromes including arthritis (termed caprine arthritis- CA), mastitis, interstitial pneumonia, encephalitis and/or myelitis (termed leukoencephalomyelitis- LEM) (Kennedy-Stoskopf et al., 1987, Maxie and Jubb, 2007). Goat kids 2–4 months of age most commonly manifest the neurologic variant, LEM (Maxie and Jubb, 2007). LEM in young dairy goats is the disease syndrome initially described for CAEV (Cork, 1976, Cork and Davis, 1975, Cork et al., 1974a, Cork et al., 1974b). Clinically, LEM affected goat kids demonstrate paraparesis often progressing to tetraparesis (Cork, 1976). Since the initial description, the neurologic forms of both CAEV and MVV have been regarded as less common than other disease manifestations (Zink and Johnson, 1994).

At present, a satisfactory rationale as to why CAEV demonstrates different anatomic and pathologic manifestations in different animals has not been advanced. Viral tissue tropism, as determined by the viral promoter, may help to explain the variation in the chronic disease syndromes of CAEV. In all lentiviruses, the viral promoter is encoded within the U3 region of the long terminal repeats (LTR). In retroviruses such as MVV and the human immunodeficiency virus-I (HIV-1), a tissue predilection has been observed for specific viral promoter sequences (Agnarsdottir et al., 2000). Nucleotide sequence divergence within the MVV promoter leads to viral isolates with distinct transcriptional activities and distinct biological behaviors (Barros et al., 2005). Brain-derived HIV-1 LTRs preferentially contain specific U3 region enhancer elements, suggesting that these sites play an important role during invasion and maintenance of HIV-1 in the central nervous system (Ross et al., 2001). Finally, the viral promoter of the ovine retrovirus Jagsiekte Sheep Retrovirus (JSRV) has been shown to be preferentially active in pulmonary type II pneumocytes and Clara cells, thereby defining viral tissue tropism and viral gene expression (Palmarini et al., 2000).

Although certain nucleotide motifs within the CAEV U3 promoter region are conserved across viral strains, numerous mutations within the viral promoter have been identified in field isolates. Considering that nucleotide sequence variation in the viral promoter has been previously shown to affect tissue tropism and disease pathogenesis for other retroviruses, we propose the hypothesis that nucleotide sequence variation in the CAEV promoter region is associated with tissue tropism and viral pathogenesis.

For this study, we retrospectively identified CAEV-infected caprine tissues from the tissue archives of multiple research institutions. Formalin-fixed, paraffin-embedded tissues confirmed to be CAEV infected by consistent histological lesions, immunohistochemistry and/or antemortem serologic results were processed for genomic and proviral DNA isolation. The CAEV U3 promoter (integrated proviral DNA) was amplified from the isolated genomic DNA using the polymerase chain reaction. The resulting viral promoter amplicons were sequenced and compared phylogenetically.

Section snippets

Animals

Histological slides of tissues from a total of sixty-one goats with an antemortem or postmortem diagnosis of CAEV were evaluated from the archives of multiple institutions: University of California Davis Veterinary Medical Teaching Hospital, California Animal Food Health and Safety Laboratory (CAHFS) Davis, Washington State University and the University of Minnesota Veterinary Diagnostic Laboratory. Tissues from an additional four animals were included from the archives of Dr. L. Cork (Stanford

Histology and immunohistochemistry

Twenty-three of the sixty-one goats demonstrated histological lesions which were also immunohistochemically positive for CAEV antigen expression in at least one tissue. Lesions considered to be histologically consistent with CAEV infection include a multifocal to diffuse histiocytic and lymphocytic inflammatory infiltrate that may efface and replace the normal tissue architecture. Synovial lesions are characterized by synoviocyte proliferation, massive infiltration of mononuclear cells,

Discussion

This study provides evidence refuting the hypothesis that nucleotide sequence variation within the CAEV promoter region is associated with tissue tropism and viral pathogenesis. Notably, CAE viral promoter sequences derived from nervous system tissues are distributed throughout the dendrogram. A similar lack of clustering was noted for viral sequences isolated from lung, joint synovium and mammary gland (Fig. 3). The study hypothesis requires that viral promoter sequences isolated from

Acknowledgements

We would like to thank Drs. N.J. Maclachlan and I. Hotzel for review of this manuscript. We are grateful for the histopathologic and immunohistochemical expertise provided by the UC Davis Histopathology Laboratory and the California Animal Health and Food Safety Laboratory (CAHFS), Davis. We also thank Drs. Linda Cork (Department of Comparative Medicine, Stanford University), Marie Gramer (Minnesota Veterinary Diagnostic Laboratory) and collaborating pathologists at the California Animal Health

References (25)

  • L.C. Cork

    Differential diagnosis of viral leukoencephalomyelitis of goats

    J. Am. Vet. Med. Assoc.

    (1976)
  • L.C. Cork et al.

    Ultrastructural features of viral leukoencephalomyelitis of goats

    Lab. Invest.

    (1975)
  • Cited by (26)

    • Nervous System

      2016, Jubb, Kennedy & Palmer's Pathology of Domestic Animals: Sixth Edition
    • Modulation of the long terminal repeat promoter activity of small ruminant lentiviruses by steroids

      2014, Veterinary Journal
      Citation Excerpt :

      In the U3 region (upstream of GR/PR5), GR/PR sites tended to be in the proximity of Myb sites, which interact with the GR/PR site in pre-B acute lymphoblastic leukaemia (Sarvaiya et al., 2012). The LTR appears to direct viral tropism (Murphy et al., 2010), although other viral proteins, such as env encoded polypeptides, may be involved in tissue tropism (Ramírez et al., 2012). The effects of steroids observed in the present study were unrelated to the body site from where the strains were isolated, and no common pattern could be inferred for strains having a common origin.

    • Impact of maedi-visna in intensively managed dairy sheep

      2013, Veterinary Journal
      Citation Excerpt :

      While epidemiological data do suggest a heritable component to resistance to MV infection (Leginagoikoa et al., 2010), in our study both flocks were comprised of sheep of the Assaf breed and the same rams were frequently used in both, suggesting all the animals studied had a similar genetic background. The tropism of the small ruminant lentiviruses (i.e. MV and CAE virus) for particular tissues could be determined by genetic variations in viral strains (Narayan et al., 1974; Straub, 2004; Oskarsson et al., 2007; Murphy et al., 2010), and the possibility remains that different strains were at large in these flocks. However, the geographical proximity of the two flocks, and the shared use of rams for breeding, would tend to suggest that similar strains would be circulating in both flocks.

    View all citing articles on Scopus
    View full text