Shared autonomous HERV loci transcription identifies a unique circulating CD14+-xCR1+ mononuclear cell phenotype in a patient group with post-acute sequelae of COVID-19

The human genome contains approximately 3,200 near full-length autonomous human endogenous retroviral (HERV) loci capable of transcriptional activation through long terminal repeats. In our previous study, we developed the Window-based HERV Alignment (WHA) method to detect locus-specific HERV transcription from single-cell RNA sequencing (scRNA-seq) data. Using WHA, we previously identified patterns of autonomous HERV loci expression in monocytes from 12 patients with post-acute sequelae of COVID-19 (PASC). In the current study, we extended the analysis to peripheral blood mononuclear cells (PBMCs) from the same 12 PASC patients. In contrast to monocytes, no consistent HERV locus transcription patterns were found across B, T, natural killer, or dendritic cells. Subsequent analysis showed that the majority of expressed HERV loci were detected in CD14 + monocytes rather than CD16 + monocytes. Four HERV loci were identified in CD14 + monocytes and were absent in CD16 + , B, T, natural killer, and dendritic cells. One of the four, the HERV locus at Chr3:46,046,256–46,054,342 was also detected in bronchial lavage cells from COVID-infected individuals but not in normal lung or tuberculosis lung tissues. The HERV locus Chr3:46,046,256–46,054,342 is located within an intron of the host gene xCR1. xCR1 expression, a marker of mature dendritic cells, was detected in CD14 + PBMCs from 11 of 12 PASC patients. These findings suggest the presence of an atypical myeloid population in PASC and may inform future strategies to evaluate persistent immune dysfunction.