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