Permissiveness of different TMEM154 genotype cell lines to different SRLV genotypes/subtypes

Small ruminant lentiviruses (SRLVs) are a heterogeneous group of viruses that infect goats and sheep worldwide, for which no cures or effective vaccines are available. Control measures have been based on early diagnosis and accurate management with limited success due to re-emergence of seropositivity and disease in controlled flocks. Association between the genetic variation in the ovine transmembrane 154 (<i>TMEM154</i>) gene and susceptibility to certain viral subtypes was previously demonstrated, representing a possible control strategy to reduce infection prevalence in sheep. Thus, the identification of the resistance spectrum of E35K SNP within <i>TMEM154</i> genotypes toward SRLV subtypes becomes crucial. In this study, 10 skin fibroblastic cell lines, from animals encoding three genotypes of the <i>TMEM154</i> (E35K) SNP, were infected with 8 SRLV viral strains and tested for the presence of retrotranscriptase (RT) activity and cytopathic effect. Additionally, SRLV entry into cells was evaluated using viral pseudotypes. Two out of the eight viral strains showed fewer syncytia, reduced cell fusion degree, and lower RT activity in the supernatant of homozygous KK cell lines, suggesting a resistant pattern in these cells. The entry assay revealed a statistically significant difference between the three cell lines in seven of the eight strains, suggesting an entry blockade as the primary restriction factor in KK cells. These findings support the potential use of the <i>TMEM154</i> gene as a marker for the genetic selection of resistant animals to specific SRLV subtypes. Moreover, the <i>ex vivo</i> approach was validated as a valuable tool for studying resistance patterns against different SRLV strains.IMPORTANCESmall ruminant lentiviruses are worldwide spread pathogens that impact animal health and result in severe economic losses. Considering the high genetic and antigenic variability of these viruses and the absence of an effective cure or vaccine, the genetic selection of resistant animals based on the <i>TMEM154</i> gene represents an interesting opportunity to control the infection. Thus, this study aimed to investigate further the host-pathogen interaction considering the association between the animal genotype for the suggested protective mutation and the infecting virus genotype using an <i>in vitro</i> model. The study confirmed <i>TMEM154</i> genetic variation as a helpful predictive factor for SRLV susceptibility by particular SRLV strains including the highly pathogenic B1 subtype, while susceptibility to some A and the B2 subtypes was not affected by the <i>TMEM154</i> gene. Once more, it highlighted the importance of monitoring circulating viral variants for the effective control of SRLV infection through genetic selection programs.