Abstract
Human endogenous retroviruses (HERVs) are under genomic and epigenetic control but can be expressed in normal tissues, producing RNA transcripts some of which are translated. While it has not been demonstrated experimentally in modern humans, cDNA copies from HERV RNA (namely HERV-K HML-2 or HK2) were produced after the human-chimp split and until at least 250,000 years ago. We were interested in determining if such cDNA could be a ligand for pattern recognition receptors (PRRs) of the innate immune response. The AIM-2-like receptors for DNA, interferon-γ-inducible protein 16 (IFI16) and Cyclic GMP-AMP synthase (cGAS) were candidate PRRs. IFI16 can detect cDNA produced during HIV-1 replication, causing increased T cell death. While HIV-1 has emerged relatively recently as a human pathogen, the cDNA functionality of IFI16 could have been selected for during the course of human evolution. Here we present a novel hypothesis that the products of reverse transcription of HK2, which has been proliferating in the genome of human ancestors for 30 million years, could interact with IFI16. In support of our hypothesis, we provide preliminary data showing that IFI16 (but not cGAS) interacts with synthetic single-stranded HK2 oligos corresponding to the first product of reverse transcription. Further, we show that ssDNA detection by IFI16 has variability with respect to sequence features but is not dependent on strong secondary structures mimicking dsDNA. Among the HK2 oligos, IFI16 interacts more intensely with those derived from LTRs, suggesting these oligos have undetermined structural features that allow IFI16 to bind with greater affinity. Further, cells with stem cell features that naturally allow HK2 expression were found to express many components of the innate immune system including cGAS but not IFI16. Based on the presented preliminary data we further postulate another hypothesis: that the IFI16 functionality in human cells has been acting as “second-line” defense to control abnormal HK2 replication in somatic tissues. The absence of this protein in stem cells and a stem cell line could permit these cells to express HERVs which contribute to stem cell identity. Finally, we also comment on potential studies that could support or refute our hypothesis.
Highlights
Retroviral proliferation in somatic tissues can be detrimental to the host
While it is known that human endogenous retroviruses (HERVs) are transcribed, it is unclear whether HERV cDNA is made in present-day humans and under which circumstances
If HERV cDNA is produced, it could be immunogenic and we have shown that it could be a ligand for IFNγ-inducible protein 16 (IFI16)
Summary
Retroviral proliferation in somatic tissues can be detrimental to the host. Both endogenous and exogenous retroviruses have been shown to be responsible for tumorigenesis and immunodeficiencies (Coffin et al, 1997). We have shown that recent (i.e., within the last 10 million years) endogenous retrovirus (ERV) proliferation activity is negatively correlated with mammalian body size, suggesting a negative impact of retroviral activity within somatic tissues (Katzourakis et al, 2014). ERVs may survive in the long term by constant germline proliferation (Magiorkinis et al, 2015), suggesting that survival of the host until reproductive age is advantageous for ERVs. It is reasonable to hypothesize that the relatively higher activity during early life events (allowing for proliferation in the germline) compared to a lower activity in somatic tissues (minimizing the pathogenic effects) is advantageous for both the host and the ERV. RNA-Seq analysis of a teratocarcinoma cell line (Tera1) revealed the extent of HK2 expression from multiple loci and the activity of many of the LTRs in driving expression (Bhardwaj et al, 2015)
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