How Retroviruses and Retrotransposons in Our Genome May Contribute to Autoimmunity in Rheumatological Conditions

Figure 1. The mechanism by which new HERVs were generated. An infectious free retrovirus infects a host germline cell, releases its circular RNA genome, which remains protected by the associated gag-derived nucleocapsid and other core proteins, while the pol-encoded RT synthesizes the first strand of linear cDNA starting with the LTR and ending after the second copy of the LTR, followed by second strand synthesis. The resulting dsDNA of approximately 9,500 bp is then inserted into the genome by the endonuclease activity of the Pol protein. The ends are then finalized by the DNA repair machinery with a few added nucleotides. Over evolutionary times, further changes to the HERVs included the accumulation of point-mutations (some introducing stop-codons), deletions by homologous recombination, and disruption by additional insertions.

Figure 2. The biology and replication cycle of the L1 element. Approximately, 500,000 copies of the L1 element, most of them truncated and mutated, exist in the human genome across all chromosomes, both within introns of protein-coding genes and in intergenic regions. Transcripts of the few 6-kb full-length L1 loci that retain intact open-reading frames are translated into the p40/ORF1p and p149/ORF2p proteins, which assemble in approximately a 20:1 stoichiometry into complexes with high affinity for RNA, particularly L1 mRNA, as well as Alu RNA. The complexes also include at least 10 other proteins, including Ro60 and La. Under permissive conditions, the RT activity of ORF2p makes a DNA copy of the associated RNA and inserts it into the genome, resulting in a new L1 element, a new Alu element, or a new pseudogene of an accidentally captured other mRNA.

Figure 3. The main proposed mechanisms by which HERVs and L1s may cause immune responses that could escalate to autoimmune disease if they become chronic or recurring. (A) starting at the bottom (intracellularly): environmental or internal factors first reduce the suppressive DNA methylation of 5’ LTRs allowing transcription factors such as those regulated by female hormones to actively transcribe one or several HERV loci. The resulting transcripts are spliced and processed and some of them are translated into proteins, while others can associate with antisense RNA, small interfering RNAs of the miRNA or piRNA classes, or form internal loop structures that are recognized by ZBP-1 (or other sensors or RNase-based enzymes), which can signal through IRF3 to IFN production or, alternatively, via the RIP3 kinase pathway to cell death by necroptosis. HERV proteins can assemble into more or less complete virions that may remain exposed on the cell surface or even bud off as mature virions. These proteins can be degraded and processed for antigen-presentation on class I or II MHC molecules to activate T cells and B cells to generate both cellular and humoral immunity. Both arms target cells…