Small Ruminant Lentiviruses: Strain Variation,Viral Tropism,and Host Genetics Influence Pathogenesis

The goal of this editorial is to provide a brief and general overview of small ruminant lentiviruses (SRLVs) and highlight the importance of research such as that by Pinczowski et al, ¹¹ published in this issue of Veterinary Pathology, in advancing our understanding of how host genetics, viral genetics, and tissue tropism influence transmission and viral pathogenesis. SRLVs are of global distribution and economic importance to sheep and goat producers. SRLVs include caprine arthritis and encephalitis virus (CAEV), maedi-visna virus (MVV), and MVV’s North American counterpart, ovine progressive pneumonia virus (OPPV). These viruses belong to the genus Lentivirus, of the Retroviridae family, and are characterized by a few proteins (including reverse transcriptase) that accompany an 8.4- to 9.2-kB genome of 2 identical single-strand RNA chains containing 6 genes, enclosed within a capsid, surrounded by an envelope that holds glycoproteins important for attachment and invasion into host cells of the monocyte lineage (monocytes, macrophages, dendritic cells, and microglia). Considering the relatively simplistic composition of these viruses, SRLVs are biologically fascinating in their ability to induce differing disease presentations, as alluded to by their viral names. Infection is lifelong, and as the genus nomenclature implies (lentus; Latin for “slow”), these viruses cause slowly progressive (months to years) disease, which may or may not manifest clinically within the host’s lifetime. MVV was named for its clinical presentations of chronic respiratory disease and neurologic disease (maedi = shortness of breath; visna = shrinkage or wasting resulting from meningoencephalitis). CAEV was also appropriately named for its ability to produce arthritic and/or neurologic disease. While once believed to be species specific, with MVV/OPPV infecting sheep and CAEV infecting goats, cross-species transmission and coinfections have been documented. As a broad generality, chronic interstitial pneumonia is more commonly observed in sheep, encephalitis and arthritis more often in goats, and indurative mastitis in both species. However, both viruses are capable of causing any of the mentioned disease manifestations.

Transmission

Mammary tissue tropism and subsequent viral shedding in colostrum and milk provide a primary source of vertical transmission from the infected host to offspring. Separation of neonates prior to suckling and pasteurization of colostrum prior to feeding, followed by hand/artificial rearing, are a means of controlling infection. However, not all transmission events can be accounted for by the colostrum/milk route of vertical transmission. Albeit less frequently, SRLVs have also been identified in secretions/excretions from the respiratory tract, urogenital tract (urine, vaginal mucus, semen), and digestive tract (feces), providing potential sources of horizontal transmission. Homing of infected monocyte lineage cells and release of virions at these epithelial/mucosal sites make them feasible sources of transmission. ⁴ Therefore, lifelong separation from carriers and strict screening prior to introduction of new animals are necessary for control and prevention of infection within a flock/herd.

The multiple routes of possible transmission, a delay between infection and detectable serum antibodies, slow disease progression, and rapid development of viral genetic variation (discussed next) have made control difficult and global—or even regional—eradication seemingly out of reach. This is particularly true for large-scale small ruminant operations or those without available means to perform necessary diagnostic testing (serology and/or quantitative polymerase chain reaction for proviral identification), artificial rearing and separation, or the more radical strategy of complete culling and replacement.

Virus Genetics

Rapid development of point mutations (because the viral reverse transcriptase lacks proofreading capabilities) and recombination events, within host cells during coinfections, are sources of rapid genetic variation, strain diversity, and virus evolution. A classification system for genotyping and subtyping SRLVs includes 5 genotypes (A through E), which have 25% to 37% variation in nucleotide sequence. ⁸ A, B, and E genotypes are further divided into at least 20 currently recognized subtypes (A1-15, B1-3, and E1-2). Most of these genotypes and subtypes have been detected in both sheep and goats, while the 2 E subtypes and 6 of the A subtypes thus far appear species limited to either sheep or goat. This may indicate that some genotypes are truly host specific or that the cross-species infection has not yet occurred or perhaps has just not yet been identified. Naturally occurring cross-species events may go undetected, unless a noticeable change in disease manifestation occurs. For example, one of the strains analyzed by Pinczowski et al ¹¹ was isolated from the first outbreak of SRLV arthritis in sheep in Spain and was identified as a CAEV-like B2 genotype. ^2,10

Host Genetics

With limitations to management control strategies, no cure/treatment, and no available vaccines to protect against either infection or disease, host genetics may prove to be a promising addition to SRLV control strategies. Previous research has shown that although SRLV viral load is positively correlated with lesion severity in the host, significant breed differences in proviral concentrations indicate a host genetic component in susceptibility. ^5,6 Although complete resistance would be the ideal host genetic trait, genetics that enable the host to maintain low viral load would be beneficial to decrease the overall consequence of disease. Maintenance of a low viral load may also be beneficial by decreasing risk of transmission to susceptible hosts. Genome-wide association studies (GWAS) can be used to identify host genotypes/polymorphisms that are associated with favorable phenotypes, such as resistance to SRLV infection or low host viral load. Identifying genotypes associated with favorable phenotypes can then be used for genetic marker–assisted selective breeding. Obviously, the steps before, between, and after GWAS and genetic marker–assisted selective breeding are far more complex than a few sentences can describe. Genetic marker–assisted selective breeding for SRLV control was reviewed in 2013 by White and Knowles. ¹³ An example, and to my knowledge the only one reported to date, of a GWAS-identified gene polymorphism that associates with decreased SRLV susceptibility or lower proviral load in sheep is found in the transmembrane 154 gene (TMEM154), a gene that encodes for a protein of unknown function. ^1,3 Since consideration of both host and virus is important in designing a control strategy, consideration for host genetic marker–assisted selection should also consider the rapid mutation and evolution that may allow SRLVs to overcome the host’s purpose-bred resistance.

Over the past decade, a number of reviews have been published on the topic of SRLVs that provide everything from the basics of the virus to detail on viral genetics, transmission, pathogenesis, and so on (a limited selection are referenced here). ^{7 –9,12} Future discoveries and advances in understanding the biology of SRLV-host interactions are essential in identifying means to control viral transmission, the resultant disease manifestation, or both.