Mixed retrovirus infections,interactions of retroviruses with the host and role of endogenous viruses in autoimmune diseases

National Institute Of Allergy And Infectious Diseases

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Abstract

In fiscal year 2021 we found a correlation between expression of an endogenous retrovirus (ERV) and diabetes in mice. ERVs are remnants of ancient retroviruses that have been incorporated into the genome and we now present evidence that islet expression of a specific ERV gene may play a role in the etiology of type 1 diabetes (T1D). We previously identified a murine leukemia retrovirus-like ERV whose Env and Gag antigens are involved in autoimmune responses in non-obese diabetic (NOD) mice. In this study, we show that the Gag antigen is present in the islet stromal cells. Although Gag gene transcripts were present, Gag protein was not detected in diabetes-resistant mice. Cloning and sequencing analysis of individual Gag genes revealed that NOD islets express Gag gene variants with complete open-reading frames (ORFs), in contrast to the diabetes-resistant mice, whose islet Gag gene transcripts are mostly non-ORFs. Importantly, the ORFs obtained from the NOD islets are extremely heterogenous, coding for various mutants that are absent in the genome. We further show that Gag antigens are stimulatory for autoreactive T cells and identified one islet-expressing Gag variant that contains an altered peptide ligand capable of inducing IFN-gamma release by the T cells. The data highlight a unique retrovirus-like factor in the islets of the NOD mouse strain, which may participate in key events triggering autoimmunity and T1D.