Inhibition of type Interferon production by murine leukemia retrovirus (MuLV)

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The innate immune system senses viral RNA via various pattern recognition receptors such as Toll-like receptors (TLR) and RIG-I like helicases (RLH) leading to subsequent immune activation and antiviral type I interferon production. RNA modifications such as 2-O-methylation or N6-methyladenosine (m6A) antagonize or negatively modulate TLR-mediated RNA recognition and may serve as immune evasion strategies for viruses. Importantly, murine leukemia virus particles or isolated genomic RNA will not stimulate murine or human plasmacytoid dendritic cells (pDCs) to produce IFN-alpha. This proposal addresses the potential role of RNA modifications in the modulation of TLR-mediated retroviral RNA recognition. Especially the role of genomic m6A methylation or 2-O-methylation of host cell-derived transfer RNA (tRNA) that is packed into viral particles and serves as primer for reverse transcription will be investigated. MuLV may also affect IFN-alpha production on an additional level, since we have observed that coincubation of MuLV with stimulating TLR ligands such as CpG-DNA leads to inhibition of IFN-alpha production in pDCs. The molecular mechanism of this inhibition will be analyzed in detail. Overall, this analysis will provide a more sophisticated understanding of the immune response to retroviruses and may lead to new approaches for antiviral drug development.