POS0312 ENDOGENEOUS HUMAN HERPESVIRUS 6B INTEGRATED IN HUMAN GENOME SEQUENCE ASSOCIATES WITH AFFECTION AND SEVERITY OF SYSTEMIC LUPUS ERYTHEMATOSUS
Authors: Y. Okada, N. Sasa, S. Kojima, T. Hasegawa, H. Namkoong, T. Hirota, R. Watanabe, K. Sonehara, R. Edahiro, Y. Shirai, Y. Maeda, M. Ishii, R. Koike, A. Kimura, H. Inohara, M. Fujimoto, S. Ogawa, T. Kanai, A. Morita, F. Matsuda, A. Kumanogoh, Y. Tanaka, K. Ohmura, K. Fukunaga, S. Imoto, S. Miyano, N. Parrish
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> 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. <h3>Objectives:</h3> 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. <h3>Methods:</h3> 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 <i>All of Us</i> WGS datasets (<i>n</i> &gt; 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). <h3>Results:</h3> 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, <i>P</i> = 0.0061 and OR = 7.0, <i>P</i> = 0.0075, respectively; Figure 2A). Replication studies using the <i>All of Us</i> WGS datasets confirmed an elevated SLE risk of eHHV-6B (OR = 2.7, <i>P</i> = 0.0020 for European ancestry, and OR = 2.4, <i>P</i> = 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; <i>P</i> = 1.3×10<sup>−8</sup>; 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, <i>P</i> = 2.6×10<sup>−8</sup>, 2.5×10<sup>−5</sup>, and 0.0042, respectively). <h3>Conclusion:</h3> 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. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>