Fig. protein that in an immune complex with SLE IgG is capable of activating neutrophils. Introduction Systemic lupus erythematosus (SLE) is a complex and variable autoimmune disease that affects predominantly women of childbearing age. Hallmarks of disease include autoreactive T and B cells, immune complex deposition in tissues, and systemic GPDA activation of type I IFN signaling and cytokines (Tsokos et al., 2016). Billions of dollars have been spent on research and development and clinical trials over the past few decades, yet belimumab (monoclonal antibody against B-cell-activating factor of the tumour-necrosis-factor family, BAFF) is the only US Food and Drug AdministrationCapproved targeted biological therapy for SLE (Navarra et al., 2011; Furie et al., 2011), and there is a great need to develop new effective therapies (Merrill et al., 2018). Endogenous retroviruses (ERVs) are retroviral sequences that originated from exogenous retroviruses that integrated into our ancestral genome 2 to 40 million years ago and have persisted through generations (Stoye, 2012). ERV sequences make up as much as 8% of the human genome, in contrast to the 2% that encodes proteins (Lander et al., 2001). Exogenous retroviral genomes originally integrated as proviral GPDA sequences, similar to HIV, but most of the now endogenous sequences have acquired mutations over the course of evolution and rendered them replication incompetent (Stoye, 2012). In fact, roughly 90% of the ERV sequences that amount to hundreds of thousands of copies in the genome are solo LTRs resulting from homologous recombination between the 5 and 3 LTRs. A minority of ERVs represented by a few thousand copies have a relatively intact proviral structure, composed of some or all of the original open reading frames (Tristem, 2000; Subramanian et al., 2011; Schmitt et al., 2013a, 2013b; Vargiu et al., 2016). Solo LTRs carry out important gene regulatory functions as alternative promoters and enhancers. They are proposed to have contributed to species evolution through the regulation of host gene networks and critical host genes, most notably those involved in embryogenesis and stem cell development (Feschotte, 2008; Jern and Coffin, 2008; Schlesinger and Goff, 2015; Chuong et al., 2017; Fuentes et al., 2018). Proviral ERVs have gained growing interest due to their association with diseases such as cancer and neurodegenerative diseases, with particular emphasis on the ERV-K family of ERVs, also known as GPDA HML-2 (Subramanian et al., 2011; Schmitt et al., 2013b; Garcia-Montojo et al., 2018). ERV-Ks are the only ERVs that are human specific with intact open reading frames, two of which remain unfixed in the human population (K113 and K115; Jha et al., 2011; Wildschutte et al., 2016; Li et al., 2019). In addition, ERV-Ks are the only ERVs reported to generate viral-like proteins GPDA in teratocarcinoma cell line and human blastocysts (L?wer et al., 1993; Bhardwaj et al., 2015; Grow et al., 2015). ERV expression is largely suppressed epigenetically in somatic cells, but aberrant expression of ERVs has been implicated in disease, including SLE pathogenesis. Viral antigen related to the primate p30 gag protein is present at sites of active lupus glomerulonephritis (Mellors and Mellors, 1976). Antibody reactivity against whole virions or gag and env peptides from murine leukemia virus and baboon ERV (Blomberg et al., 1994) and ERV-derived ERV-9 and HRES-1 peptides (Bengtsson et al., 1996) are also observed in SLE. Roughly half of the SLE patients have reactivity against a 28-kD nuclear autoantigen (p28) that is encoded by a human T cell lymphotropic GPDA virusCrelated endogenous sequence (HRES-1; Banki et al., 1992; Perl et al., 1995; Perl et FGFR3 al., 2008). Several haplotypes of HRES-1 contained in the.