ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Endocrinology 2019;160:2165–2179

This paper characterize viral insulin/IGF-1–like peptides (VILPs), which the authors identified in four members of the Iridoviridae family - viruses with double-stranded DNA genomes, which are found in amphibians, fish, and invertebrates. VILPs can bind to human insulin and IGF-1 receptors and stimulate classic post-receptor signaling pathways. They can stimulate glucose uptake in vitro and in vivo and stimulate DNA synthesis. DNA sequences of some VILP-carrying viruses have been identified in the human enteric virome.

Mimicry is a common evolutionary principle that occurs to gain an advantage in competing for resources, protection, or survival. Viruses use mimicry to their benefit by expressing molecules that resemble host growth factors or immune response regulators and their receptors. Using a bioinformatics approach, this paper reports that viruses possess the DNA/RNA with potential to encode 16 different peptides with sequence similarity to human peptide hormones and metabolically important regulatory proteins including VILP and α-melanocyte-stimulating hormone. Two of these VILPs bind to the human IGF1 receptor (hIGF1R) with a better affinity than human insulin, but with a less affinity than human IGF-1. VILPs also compete for the human insulin receptor (hIR), but were much weaker affinity than human insulin and even human IGF-1. Consistent with this, all VILPs tested stimulated receptor autophosphorylation with higher potency on hIGF1R than on the human IR. All VILPs stimulated glucose uptake, even if at lower potencies than insulin and IGF-1. Thus, despite the low binding affinity to the hIR, VILPs stimulate biological function, suggesting that these peptides may bind to receptors in some unique way compared with the mammalian hormones.

One mechanism of viral mimicry uses divergent evolution involving the transfer of a gene from a host genome to a viral genome via horizontal gene transfer. Another aspect of viral mimicry generates proteins that affect the host immune system by imitating the function of cytokines such as IL-6, IL-10, and IL-17.

The authors suggest that a potential consequence of VILPs in humans is in the pathogenesis of Type 1 diabetes (T1D). These viral peptides might stimulate or desensitize T-cells and thus contribute to the pathogenesis of T1D by triggering T-cell cross-reactivity with endogenous insulin.