POS0312 ENDOGENEOUS HUMAN HERPESVIRUS 6B INTEGRATED IN HUMAN GENOME SEQUENCE ASSOCIATES WITH AFFECTION AND SEVERITY OF SYSTEMIC LUPUS ERYTHEMATOSUS

• Published in: Annals of the rheumatic diseases Vol. 83; no. Suppl 1; pp. 262 - 263
• Main Authors: Okada, Y., Sasa, N., Kojima, S., Hasegawa, T., Namkoong, H., Hirota, T., Watanabe, R., Sonehara, K., Edahiro, R., Shirai, Y., Maeda, Y., Ishii, M., Koike, R., Kimura, A., Inohara, H., Fujimoto, M., Ogawa, S., Kanai, T., Morita, A., Matsuda, F., Kumanogoh, A., Tanaka, Y., Ohmura, K., Fukunaga, K., Imoto, S., Miyano, S., Parrish, N.
• Format: Journal Article
• Language: English
• Published: Kidlington BMJ Publishing Group Ltd and European League Against Rheumatism 01.06.2024; Elsevier Limited
• Subjects: Alveoli; Antiviral drugs; Autoimmune diseases; Biomarkers; Coronaviruses; COVID-19; Datasets; Disease; Embedding; Epigenetics, Genetics; Genomes; Herpes viruses; Immune response; Infectious diseases; Innate immunity; Leukocytes (mononuclear); Lupus; Microbiome; Monocytes; Multiple sclerosis; Nucleotide sequence; Peripheral blood mononuclear cells; Phenotypes; Psoriasis vulgaris; Replication; Rheumatoid arthritis; Ribonucleic acid; RNA; Scientific Abstracts; Systemic lupus erythematosus; Viral infections; Whole genome sequencing
• ISSN: 0003-4967; 1468-2060
• DOI: 10.1136/annrheumdis-2024-eular.1619

Background:Aberrant immune responses to viral pathogens contribute to disease pathogenesis. However, the link between endogenous viruses or viral infection and autoimmune diseases is a longstanding mystery in the fields of basic and clinical science.Objectives:To clarify whether and which viruses comprising human viromes influence pathological immune responses and confer autoimmune disease risk. To validate clinical impacts of human virome as biomarkers of the autoimmune diseases.Methods:We analyzed whole-genome sequencing (WGS) datasets of human genomes of 6,321 Japanese individuals, including those with autoimmune diseases (psoriasis vulgaris [PV], rheumatoid arthritis [RA], systemic lupus erythematosus [SLE], pulmonary alveolar proteinosis [PAP], or multiple sclerosis [MS]) and severe coronavirus disease 2019 (COVID-19), or healthy controls (HC). We systematically quantified two constituents of the blood DNA virome, endogenous human herpesvirus 6A and 6B (eHHV-6A/B) integrated in the individuals’ human genome sequences and anellovirus. We then conducted disease case–control association studies (Figure 1A). Replication studies were conducted using the All of Us WGS datasets (n > 240,000). Single-cell RNA sequencing (scRNA-seq) data of peripheral blood mononuclear cells (PMBCs) from the four eHHV-6B-positive patients with SLE and 11 eHHV-6B-negative patients with SLE were compared (Figure 1).Results:We successfully detected eHHV-6A/6B (prevalence of 0.2% and 0.1% in HC, respectively) and anellovirus (12.3%, 1.0%, and 0.29% for anellovirus-detected, -infected, and -viremic, respectively). Subjects with eHHV-6B had significantly higher risks of SLE and PAP (odds ratio (OR) = 6.9, P = 0.0061 and OR = 7.0, P = 0.0075, respectively; Figure 2A). Replication studies using the All of Us WGS datasets confirmed an elevated SLE risk of eHHV-6B (OR = 2.7, P = 0.0020 for European ancestry, and OR = 2.4, P = 0.0012 for multi-ancestry). eHHV-6B and high SLE Disease Activity Index (SLEDAI) scores had strong correlations (mean SLEDAI = 30.5 and 6.0 for eHHV-6B-positive and -negative patients with SLE, respectively; P = 1.3×10−8; Figure 2B). Single-cell RNA sequencing showed increased antiviral interferon-stimulated gene (ISG) expression profiles of monocytes in the eHHV-6B-positive patients with SLE when compared with those of the eHHV-6B-negative (Figure 2C, 2D). In addition, strong positive correlations between high anellovirus load in blood and SLE, RA, and severe COVID-19 were observed (OR = 58.5, 15.4, and 6.2 for infected status, P = 2.6×10−8, 2.5×10−5, and 0.0042, respectively).Conclusion:Our analyses utilizing the large-scale WGS reveal previously unknown relationships between the human virome and autoimmune and infectious diseases. Individuals carrying eHHV-6 or anellovirus positivity appears to have strikingly high impacts on disease risk and clinical phenotypes of SLE, demonstrating a value as the new informative clinical biomarker.Figure 1.Overview of the study design. Japanese WGS datasets from patients with five autoimmune diseases and COVID-19 and healthy controls were analyzed to detect eHHV-6A/B and anellovirus infection, followed by replication using All of Us. We compared scRNA-seq from eHHV-6B-positive and -negative patients with SLE.Figure 2.Significantly high eHHV-6 prevalence, SLEDAI scores, and antivirus ISG of eHHV-6B-positive patients with SLE. (A) Prevalence of eHHV-6A/6B in the subject groups. The red line indicates prevalence of eHHV-6A or -6B = 1%. (B) TSLEDAI scores of eHHV-6B-positive and -negative patients with SLE. (C) Single-cell RNA-seq of PBMCs from eHHV-6B-positive and -negative patients with SLE. UMAP embedding of scRNA-seq representing immune cell types. (D) Comparisons between the antiviral ISGs scores of the eHHV-6B-positive SLE patients with those of the eHHV-6B-negative.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:None declared.