Activation of caprine arthritis-encephalitis virus expression during maturation of monocytes to macrophages

Abstract

Lentiviruses, which cause arthritis-encephalitis and maedi-visna in goats and sheep, respectively, cause persistent infections in these animals. The viruses replicate productively at low levels in macrophages in diseased organs such as the "maedi lung" and nonproductively in other cell types such as leukocytes in peripheral blood. Nonproductive infections become productive during in vitro cultivation of the cells. This study showed that monocytes were the only cells in the peripheral blood leukocytes of an infected animal in which virus was detected and that virus activation occurred only when these cells matured into macrophages. Only a minute fraction of cultured monocytes matured into macrophages, and viral infectivity was associated exclusively with this fraction. Antiglobulincoated glass wool fragments were lethal for monocyte macrophages because of toxic phagocytosis, but had no effect on B or T lymphocytes. The simultaneous addition of the glass fragments and leukocytes to culture dishes resulted in no macrophage maturation and no virus production. The addition of the fragments to virus-producing macrophages caused the death of the cells and a decline in virus production. Virus production in less avidly phagocytic cells was unaffected by the glass. Thus, although macrophages may be permissive for virus replication, one mechanism for restricted virus expression in vivo may be physiological factors controlling the maturation of these cells.

Infections and multiple sclerosis

“…Only cells of macrophage lineage are infected in the nervous system. The demyelination appears associated with an interferon-like molecule (a cytokine or lymphokine) released in the nervous system by infected macrophages and microglia (Narayan et al, 1983;Kennedy et al, 1985). The management of sheep and goats in laboratories and the lack of ruminant reagents for immunological studies have limited investigations of these models.…”

Important mammalian veterinary viral immunodiseases and their control

“…Since SRLVs do not infect lymphocytes, immunodeficiency and immunosuppression is not a significant feature in SRLV disease [38,[47][48][49]]. An important determinant in SRLV pathogenesis is virus tropism for monocytes, macrophages and dendrictic cells [49,50]. Monocytes harbouring SRLV provirus in their genomes show little or no viral transcription.…”

“…This conclusion was based on the finding of significantly reduced count of VMV-infected monocytes in sheep depleted of CD4+ T cells [55]. Maturation of latently infected monocytes to macrophages in target organs activates productive virus replication [4,50]. This occurs in selective population of macrophages in different tissues [4].…”

“…Viral LTR contains enhancer/promoter and regulatory sequences required for trans-activation of virus transcription by macrophage produced factors and is an essential determinant of the tropism and expression of SRLV disease pathogenesis [4,37] (and references therein). In VMV, the trigger involves cellular factors binding to LTR enhancer sequence AP-1 while in CAEV, LTR activation may involve interaction of TNF alpha and interferon gamma with the U3 region of the viral LTR [4,37,50,[56][57][58][59][60]. The host's genetic factors may regulate the extent of viral gene expression in tissue macrophages and thus the disease.…”

“…The viral long terminal repeat (LTR) region contain sequences for transcription initiation and mRNA capping sequences important in the regulation and control of viral mRNA synthesis. For VMV at least, the trigger involves cellular factors binding to AP-1 promoter while in CAEV, LTR activation may involve interaction of TNF alpha and interferon gamma with the U3 region of the viral LTR [4,37,50,[56][57][58][59][60]. In VMV CD4+ T cells are required to establish infection in macrophages but not in dendretic cells [55].…”