Update on Small Ruminant Lentiviruses.

Small ruminant lentiviruses (SLRVs) have been recognized throughout the world for decades. SLRVs are a heterogenous group of viruses that can infect sheep, goats, and wild ruminants. Evidence supports cross-species infection. These viruses cause lifelong infections where they target specific organs, which can result in production losses due to diminished milk production, consequential increases in neonatal death and diminished growth, and premature culling of prime age animals. No vaccine or treatments have proved effective. Control programs rely on an understanding of viral transmission and application of highly sensitive, specific, and frequent testing regimens.

Small Ruminant Lentiviruses in Sheep: Pathology and Tropism of 2 Strains Using the Bone Marrow Route.

The objective of this work was to comparatively study the tissue tropism and the associated pathology of 2 autochthonous small ruminant lentivirus (SRLV) field strains using an experimental infection in sheep through the bone marrow. Fifteen male, SRLV-free lambs of the Rasa Aragonesa breed were inoculated with strain 697 (nervous tissue origin, animals A1-A6), with strain 496 (articular origin, animals B1-B6), or with uninfected culture medium (C1-C3). Clinical, serologic, and polymerase chain reaction (PCR) evaluations were performed periodically. Two lambs from each infected group and a control animal were euthanized at 134, 273, and 319 days postinfection. Tissues were analyzed by gross and histopathologic evaluation; immunohistochemistry for CD3, CD4, CD8, CD68, and FoxP3 cell markers; lung morphometric evaluation; and tissue proviral quantification by PCR. All infected animals became positive either by enzyme-linked immunosorbent assay and/or PCR, with group B lambs showing the highest serologic values and more consistently positive PCR reactions. Group A lambs showed representative lung lesions but only mild histopathologic changes in the central nervous system (CNS) or in carpal joints. Contrarily, group B lambs demonstrated intense carpal arthritis and interstitial pneumonia but an absence of lesions in the CNS. Proviral copies in tissues were detected only in group B lambs. Experimental infection with these SRLV strains indicates that strain 496 is more virulent than strain 697 and more prone to induce arthritis, whereas strain 697 is more likely to reproduce encephalitis in Rasa Aragonesa lambs. Host factors as well as viral factors are responsible for the final clinicopathologic picture during SRLV infections.

The risk of small ruminant lentivirus (SRLV) transmission with reproductive biotechnologies: state-of-the-art review.

Reproductive biotechnologies are essential to improve the gene pool in small ruminants. Although embryo transfer (ET) and artificial insemination (AI) greatly reduce the risk of pathogen transmission, few studies have been performed to quantify this risk. The aim of this review is to contribute to the elements needed to evaluate the risk of lentivirus transmission in small ruminants (SRLV) during ET, from embryos produced in vitro or in vivo, and with the use of the semen destined for AI. The purpose is to consider the genetic possibilities of producing uninfected embryos from infected females and males or bearers of the SRLV genome. We have reviewed various studies that evaluate the risk of SRLV transmission through genital tissues, fluids, cells, and flushing media from female and male animals. We have only included studies that apply the recommendations of the International Embryo Transfer Society, to obtain SRLV-free offspring from infected female animals using ET, and the justification for using healthy male animals, free from lentivirus, as semen donors for AI. As such, ET and AI will be used as routine reproductive techniques, with the application of the recommendations of the International Embryo Transfer Society and World Organization for Animal Health.

Impact of natural sheep-goat transmission on detection and control of small ruminant lentivirus group C infections.

Dissemination of small ruminant lentivirus (SRLV) infections in Norway is affected by the different control strategies used for maedi-visna virus (MVV) infections in sheep and caprine arthritis-encephalitis virus (CAEV) infections in goats. Here we investigated SRLV phylogenetic group variants in sheep. CAEV-like isolates, belonging to phylogenetic group C, were found among both seropositive sheep and goats in mixed flocks, in which sheep and goats are kept together. Intra-herd clustering confirmed that mixed flock animals were infected by the same virus variant, suggesting ongoing interspecies transmission. Few sheep flocks were found to be infected with the MVV-like phylogenetic group A. The apparent absence of SRLV group A type in goats is probably due to the MVV control programme and animal management practices. SRLV group C targets lungs and mammary glands in sheep, and induces typical SRLV pathological lesions. SRLV group C isolated from the sheep mammary glands suggested a productive infection and potential for transmission to offspring. SRLV group C was most prevalent among goats. A lower PCR sensitivity in seropositive sheep suggested a lower load of SRLV group C provirus in sheep than in goats. Higher genetic divergence of group C than in other SRLV groups and extensive heterogeneity among group C isolates in the matrix C-terminal region demonstrate the need for identifying conserved target regions when developing PCR protocols for SRLV detection. As sheep and goats may serve as reservoirs for all SRLV genogroup types, successful control programmes require inclusion of both species.

Effects of recombinant ovine interferon-tau on ovine lentivirus replication and progression of disease.

The antiviral effects of recombinant ovine interferon-tau (roIFN-tau) were studied in 26 lambs inoculated with ovine lentivirus (OvLV) or mock-infected. Six of the OvLV-infected lambs and three of the mock-infected lambs were treated with 10(6) antiviral units (AVU) per kg roIFN-tau daily for 30 days starting at day 0 post-inoculation (p.i.) and twice a week thereafter (early treatment). Six of the OvLV-infected lambs and three of the mock-infected lambs were treated with 10(6) AVU/kg roIFN-tau daily for 30 days starting at day 150 p.i. and twice a week thereafter (late treatment). Six OvLV-infected and two mock-infected lambs were treated either early or late with placebo. Cell-associated viraemia was quantified by an end-point dilution method. The weekly antibody response against OvLV proteins was studied by ELISA. All experimental animals were killed at 27 weeks p.i. and histological sections of lung were scored for the degree of lymphoid interstitial pneumonia (LIP). A 90% reduction in OvLV titres was detected at 4 weeks post-treatment in lambs that received early roIFN-tau treatment (P<0.01). Differences in virus titres were also found at weeks 2 and 6 (P<0.05). Scores for LIP degree were higher in infected lambs treated with placebo or late roIFN-tau than in the mock-infected lambs or in the infected lambs that received early roIFN-tau (P<0.05). LIP scores were not different between mock-infected lambs and infected lambs that received early roIFN-tau. These results indicate that roIFN-tau curtails OvLV replication in vivo and reduces the likelihood of development of lentivirus-induced LIP when infected lambs are treated during the initial phases of OvLV infection.

Ovine lentivirus-infected macrophages mediate productive infection in cell types that are not susceptible to infection with cell-free virus.

Ovine lentiviruses and caprine arthritis-encephalitis virus (CAEV) are prototypic lentiviruses that replicate predominantly in macrophages of infected animals. In situ hybridization of pathologically affected tissues from diseased animals has shown that viral RNA exists in permissive macrophages as well as in non-macrophage cell types that do not support productive virus replication. These findings raise questions about the cellular tropism of these viruses in vivo and how this may relate to their pathogenesis and the establishment of persistent infections. In this study, the susceptibility of macrophages and fibro-epithelial cells derived from goat synovial membrane (GSM) to infection by 14 North American ovine lentivirus strains was examined. All 14 strains were macrophage-tropic, as indicated by expression of viral proteins and by fusion and development of syncytial cytopathic effects following co-culture of infected macrophages with GSM cells. In contrast, neither viral DNA nor viral proteins was detected in GSM cells inoculated with cell-free virus from nine of the 14 strains. Specific virus proteins were immunoprecipitated from restrictive GSM cells following culture with infected macrophages and serial passage of GSM cells to remove the macrophages. The lack of infection of GSM cells by cell-free virus from some ovine lentivirus field strains was circumvented by cell-associated virus infection from infected macrophages to GSM cells following cell-to-cell contact. This strategy could be one of the mechanisms involved in the escape from immune surveillance and establishment of persistent infection in infected animals.

Molecular biology and pathogenesis of animal lentivirus infections.

Lentiviruses are a subfamily of retroviruses that are characterized by long incubation periods between infection of the host and the manifestation of clinical disease. Human immunodeficiency virus type 1, the causative agent of AIDS, is the most widely studied lentivirus. However, the lentiviruses that infect sheep, goats, and horses were identified and studied prior to the emergence of human immunodeficiency virus type 1. These and other animal lentiviruses provide important systems in which to investigate the molecular pathogenesis of this family of viruses. This review will focus on two animal lentivirus models: the ovine lentivirus visna virus; and the simian lentivirus, simian immunodeficiency virus. These animal lentiviruses have been used to examine, in particular, the pathogenesis of lentivirus-induced central nervous system disease as models for humans with AIDS as well as other chronic diseases.