DYSREGULATION OF THE EXPRESSION OF HUMAN RETROVIRUSES IN SYSTEMIC LUPUS ERYTHEMATOSUS

PV100 / #484 Poster Topic: AS12 - Genetics, Epigenetics, Transcriptomics Background/Purpose Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease characterized by dysregulation of the immune system. Although many etiologies have been suggested for SLE, the possibility that active or latent viruses may contribute has been entertained. A family of viral elements, the Human Endogenous Retroviruses (HERVs), remnants of ancient viral infections comprising ~8% of the human genome, are possible etiologic factors in SLE. Previous studies have suggested that HERVs contribute to SLE pathogenesis by being differentially expressed in people with the disease — triggering the sensing mechanisms that detect cytoplasmic viral-like RNA and, thereby, inducing an interferon response.[1] For decades, HERVs have been classified and named by molecular and genomic features. This legacy system has little bearing on the evolutionary history and sequence features of HERV elements. We hypothesized that features of HERV immunogenicity and the role of HERVs in SLE pathogenesis would be more apparent upon regrouping HERVs in a taxonomically robust manner followed by a set of in-silico RNA-binding analyses and transcriptomic HERV quantification in SLE patients. Methods We employed sequence alignment and phylogenetic inference to align 14,000+ HERV sequences in the human genome and calculate a distance matrix for these sequences. We clustered HERVs into groups with shared sequence similarity and common evolutionary history. We characterized the sequences in these clusters using RNA-binding prediction to identify how RNA HERV transcripts would be expected to bind with sensors of innate immunity relevant to SLE pathophysiology: Rig-I, MDA5, ADAR, and ZBP. We further classified HERV sequences according to viral similarity by performing a BLAST against a database of exogenous viral genomes. HERV expression in RNAseq data from human keratinocytes stimulated with various cytokines relevant to SLE pathophysiology (TWEAK, TNF, IL-17A IFNa2, IL18, IFNa6, IFNb, and IFNg) was quantified and HERV expression was similarly quantified in 124 SLE patients and 41 healthy controls. Results We identified HERV clusters of shared evolutionary history that are dysregulated in SLE. Clusters of HERVs with specific expression patterns in SLE were also exhibited dysregulated expression in keratinocytes stimulated with inflammatory cytokines and increased binding with sensors of innate immunity. Those families of HERVs upregulated upon cytokine stimulation are the same HERVs that seem to be immunoactive, especially in terms of binding with ADAR — an intracellular enzyme known to be involved in RNA editing and regulation of interferon production. Finally, families of HERVs upregulated in SLE share sequence similarity with extant infectious viruses with known rheumatologic consequences, including alphavirus,Chikungunya. Conclusions HERVs can be separated into families based on sequence similarity. Specific families are upregulated in SLE, are induced by specific cytokines in vitro and are enriched in sequences that bind intracytoplasmic RNA sensors. Our findings support the existence of positive-feedback loops in the pathophysiology of SLE, whereby cytokines induce the expression of HERVs with molecular motifs that bind to sensors of cytoplasmic RNA and lead to further cytokine production, inflammation, and an interferon signature in SLE. Finally, these families of HERVs share sequence similarity with infectious viruses known to cause rheumatologic manifestations. References: [1.] Stearrett N. Front Immunol 2021;12:661437).

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