Caprine Arthritis Encephalitis Virus Is Associated with Renal Lesions

Abstract

Caprine arthritis encephalitis virus (CAEV) is a monocyte/macrophage-tropic lentivirus that primarily infects goats resulting in a well-recognized set of chronic inflammatory syndromes focused on the joint synovium, tissues of the central nervous system, pulmonary interstitium and mammary gland. Clinically affected animals generally manifest with one or more of these classic CAEV-associated tissue lesions; however, CAEV-associated renal inflammation in goats has not been reported in the peer-reviewed literature. Here we describe six goats with chronic, multisystemic CAEV infections in conjunction with CAEV-associated renal lesions. One of the animals had CAEV antigen-associated thrombotic arteritis resulting in infarction of both the kidney and heart. These goats had microscopic evidence of inflammatory renal injury (interstitial nephritis) with detectable renal immunolabeling for CAEV antigen in three of six animals and amplifiable proviral sequences consistent with CAEV in all six animals. Cardiac lesions (vascular, myocardial or endocardial) were also identified in four of six animals. Within the viral promoter (U3) region, known transcription factor binding sites (TFBSs) were generally conserved, although one viral isolate had a duplication of the U3 A region encoding a second gamma-activated site (GAS). Despite the TFBS conservation, the isolates demonstrated a degree of phylogenetic diversity. At present, the clinical consequence of CAEV-associated renal injury is not clear.

Keywords: CAEV; SRLV; TFBS; goat; interstitial nephritis; kidney; lentivirus; promoter.

Figure 1

Gross image of kidney, goat D. Pale, linear radiating streaks are evident in the renal cortex and medulla (interstitial nephritis and fibrosis, yellow arrowheads).

Figure 2

Histological features of CAEV-associated renal lesions (HE-stained sections). (a) A large artery at the corticomedullary junction has a luminal thrombus and is cuffed by moderate numbers of lymphocytes, (thrombotic arteritis, goat A). (b) The renal interstitium is expanded by large numbers of mononuclear lymphocytes and plasma cells (interstitial nephritis, goat B). (c) The renal cortex has an organized lymphoid follicle expanding the interstitium of goat B. (d) The medullary interstitium is infiltrated by moderate numbers of lymphocytes (interstitial nephritis, goat D).

Figure 3

Histological features of CAEV-associated cardiac lesions (HE-stained sections). (a) A large artery within the myocardium has luminal and mural fibrin deposition and periarteriolar inflammation (thrombotic arteritis, goat A). (b) The myocardium has interstitial fibroplasia/fibrosis and lymphocytic inflammation (fibrosing myocarditis, goat C). (c) Cardiomyocytes are multifocally atrophied and have pyknotic nuclei (myocardial necrosis, goat D). (d) The myocardial interstitium has a focal loss of cardiomyocytes with interstitial fibroplasia (goat D).

Figure 4

Immunohistological features of CAEV-associated cardiac and renal lesions (SRLV IHC). (a) Abundant CAEV antigen is present (brown staining granules) within the arterial tunica media (heart, goat A). (b) Moderate CAEV antigen is present within the arterial tunica media (kidney, goat A). (c) Focal CAEV antigen deposition is present within the tubular epithelium of the renal medulla (kidney, goat C). (d) Focal CAEV antigen is present within the tubular epithelium in the renal medulla (kidney, goat E).

Figure 5

Nested PCR, agarose gel electrophoresis. An appropriate-sized PCR amplicon is present in samples derived from the kidney of goat A. Molecular weight markers (lane 1), kidney (positive, lane 4), other caprine tissue samples (negative, lanes 2, 3, 5, 7), water template (negative control, lanes 6 and 8), plasmid DNA (positive control, lane 9).

Figure 6

Alignment of the six CAEV U3 sequences derived from renal tissues of goats A, B, C, D, E and F. The two A blocks (A1 and A2, red bars) containing the GAS (filled red boxes) are indicated. Other transcriptional factor binding sites are also indicated—AP-1 (3 blue boxes), TAS (purple box), AML (green box), AP4 (2 red boxes) and TATA (black box). Consensus nucleotide positions are indicated with an asterisk.

Figure 7

Schematic map of the CAEV U3 region (promoter). Promoter motifs are represented as black boxes and are named. The 70 base pair repeat (contiguous grey boxes) is broken into 4 subregions, A, B, C and D. Promoter isolates with sequence insertions are demonstrated schematically above the promoter map. CAEV sequences derived from renal isolates are in red (goats A–F); previously published sequences are in black (CAEV-A through CAEV-Z). Figure adapted with permission from BG Murphy, VM Elliott, N CVapniarsky, A. Oliver and J. Rowe (2010) [14].

Figure 8

Phylogenetic dendrogram comparing the nucleotide sequences of CAEV U3 isolates from the renal tissue of goats A–E (red arrowheads) with previously published U3 sequences—tissues of the central nervous system (green arrowhead), joint synovium (black arrowhead), mammary gland (yellow arrowhead with black border) and lung (light blue arrowhead). CAEV A–Z sequences from [14]. Figure adapted with permission from BG Murphy, VM Elliott, N CVapniarsky, A. Oliver and J. Rowe (2010) [14].