Visna/Maedi virus (VMV) and caprine arthritis encephalitis virus (CAEV) are small ruminant lentiviruses (SRLV) of the retroviridae family 
that infect sheep and goats in major sheep producing countries worldwide. The exceptions are Iceland where VMV was eradicated after a 30-year effort 
, and Australia and New Zealand where VMV has not been reported in sheep but CAEV has been reported in goats 
. Once infected, seroconversion typically occurs within weeks to months and the infection is incurable. Sheep do not usually display signs of clinical disease in the first two years of infection. The first signs of disease are often loss of body condition and indurative mastitis (i.e., thin ewe syndrome and hard udder). When disease develops, severe clinical signs may include difficulty breathing, chronic wasting, loss of motor control, and arthritis. Ovine progressive pneumonia virus (OPPV) is a closely related North American counterpart to VMV and typically produces an interstitial pneumonia. Seroprevalence studies of U.S. sheep have shown that 36% of sheep operations have infected animals and 24% of all animals tested were seropositive 
. The impact of subclinical OPPV infection is significant and includes detrimental effects on sheep production from breeding through weaning 
. Considering that losses are cumulative during an animal's lifetime, the negative effects on ewe production and the sheep industry are substantial.
Natural transmission of ovine lentiviruses is primarily among adults, occurs most frequently after their first year 
, and is by the respiratory route 
. In addition, some infections occur in lambs by ingestion of infected colostrum and milk 
. Ovine lentiviruses are macrophage-tropic but not T-lymphocyte-tropic and thus do not cause an immunodeficiency in sheep 
. Persistence of ovine lentivirus in infected sheep is attributed to latent proviral DNA sequences integrated into the genome of a small fraction of monocytes circulating in the blood. Proviral DNA transcription and gene expression is suppressed until infected monocytes mature into macrophages as they migrate into the interstitial spaces of affected organs 
. Once in the target organs, infected macrophages initiate viral replication, which induces an inflammatory cascade that ultimately attracts more infected monocytes and other leukocytes. These lesions increase progressively, terminating in disease and eventual death.
Although there is no cure, the impact of disease can be reduced by lowering the prevalence. Voluntary SRLV control programs have been established in several European countries 
. OPP can be eradicated by testing and removing infected animals or by isolating lambs from seropositive dams at birth. The lambs are then raised on uninfected colostrum and milk, and maintained separately from seropositive sheep thereafter. Either of these methods may be used alone, or in combination, to break the cycle of transmission. However, an OPP-free flock is still susceptible to infection if exposed to other infected sheep or goats 
. Thus, efforts to eradicate OPP and maintain infection-free status would be facilitated if replacement breeding stock were genetically resistant to lentivirus infections.
Examples of genetic resistance to lentivirus infection have been documented in human populations. Nearly all individuals who lack the lentivirus co-receptor CCR5 do not acquire human immunodeficiency virus (HIV) infection after significant exposure 
. Moreover, an infected person receiving transplanted stem cells lacking CCR5 may be cured of HIV 
. In the cases of VMV and OPPV, reports have suggested that host resistance to lentiviral infection may also occur in sheep 
. Significant breed effects on seroprevalence have also been observed in comingled flocks of purebred sheep, further indicating possible host genetic restriction 
. For example, in U.S. sheep the OPPV seroprevalence in purebred Finnsheep, Texel, and Suffolk was 77, 65, and 15%, respectively 
. In Basque dairy-sheep, seroconversion was strongly associated with lifetime maternal VMV-serological status and was interpreted as evidence of genetic susceptibility 
The present article reports findings from a genome-wide association study (GWAS) that used naturally-exposed ewes, together with the International Sheep Genome Consortium SNP50 marker set, to test for genetic association with lentivirus infection. Ovine DNA sequence variation in a transmembrane protein gene (TMEM154) was associated with lentivirus infection. The ancestral TMEM154 allele encodes a 191 amino acid polypeptide with glutamate (E) at position 35 and is associated with infection susceptibility. A mutant TMEM154 allele encodes lysine (K) at position 35 allele and is associated with reduced susceptibility. Two deletion mutations were also observed in TMEM154, however there were not enough individuals with these deletions to test their effect. Together, these results suggest that TMEM154 may play a central role in ovine lentivirus biology.