Background/Purpose: Human Endogenous Retroviruses (HERVs) are remnants of retroviral infections in the human germline. Most, but not all, HERV genes have become inactive by accumulation of mutations. The presence of open reading frames (ORFs) in a few select HERV genes, suggest an evolutionary advantage for the host in maintaining the protein coding capacity. We investigated whether differences could be detected between upregulation of a panel of ENV-proteins in patients with Systemic Lupus Erythematosus (SLE) compared to healthy controls. Further, we examined a peptide form of the highest upregulated ENV-protein for an anti-inflammatory potential in vitro, ex vivo and in vivo

Methods: 45 patients fulfilling the ACR criteria for SLE and 50 age and gender matched blood donors, were included consecutively. By real time PCR, we analyzed the transcriptome of 11 genes with coding capacity for complete envelope protein. Subsequently, we cloned the Env59 gene to examine if it retained its retroviral fusion protein activity. Sequence analysis of the protein identified an immune suppressive domain (ISD). A corresponding peptide was synthesized and examined in vitro for immune suppressive activity on stimulated experimental cell lines and ex vivo on human PBMCs from patients with SLE and Rheumatoid Arthritis. Next, in two separate treatment experiments, we tested the anti-inflammatory potential of the peptide in vivo in an experimental model of arthritis, the Sakaguchi mouse (first experiment n=15, second n=40). Mice were treated daily for 4 weeks. Arthritis scoring was performed blinded. At termination, hind paws were fixated in ethanol for histology and stained with Masson-Golden trichrome.

Results: We found that the HERV-H derived Env gene (Env59) was highly expressed in SLE patients. Further, that expression of Env59 showed negative correlation with the central inflammatory protein IL-6 (P=0.0065). The peptide version of the Env59 ISD had anti-inflammatory activity and ability to lower IL-6 levels in vitro and ex vivo. Lastly, in two independent in vivo experiments of experimental arthritis, we illustrated the peptide significantly lowered arthritis score (p<0.05) in treated versus untreated mice. The reduction in arthritis was confirmed measuring serum amyloid A3 as a biomarker for inflammation and by histology in mice treated with saline compared to peptide-treated mice.

Conclusion: We demonstrated an upregulation of Env59 in SLE patients compared to healthy controls, and that ENV59 expression was negatively correlated to IL-6 expression in SLE patients. With a synthetic peptide derived from the ISD domain of the retroviral gene we illustrated an anti-inflammatory potential of the peptide in vitro, ex vivo and in vivo. We propose the peptide represents a possible new treatment strategy for inflammatory diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/advantageous-effect-of-an-endogenous-retroviral-envelope-protein-in-systemic-lupus-erythematosus-with-ex-vivo-and-in-vivo-anti-inflammatory-potential/