Viral evasion of DNA-stimulated innate immune responses

Christensen, Maria H; Paludan, Søren R

Retrovirus replication leads to accumulation of several DNAcontaining nucleic acid structures with the capacity to stimulate DNA sensors. 39 Whereas the RNA:DNA intermediate has been reported to be detected by TLR9 and cGAS, 40,41 the singlestranded DNA (ssDNA) species and the final double-stranded DNA (dsDNA) products also have the potential to stimulate type I IFN expression in a manner dependent on IFI16 and cGAS. 30, 42 Viral ssDNA molecules named 'strong-stop ( − )-strand DNA' (sstDNA) are present in the cytosol upon HIV-1 infection. 43 These sstDNAs, formed by the first 181 nucleotides of the HIV-1 genome, are reversely transcribed and fold up in a secondary structure with three hairpin elements. This structure has recently been reported as a HIV-1 PAMP, stimulating type I IFN production, due to sensing by cGAS. 44 Herzner et al. 44 found that the transition from dsDNA to ssDNA, named Y-form DNA, was the stimulatory part of the sstDNA molecule. The Y-form structure stimulates the production of cGAMP and the cGAMP response was found to correlate with the numbers of guanosine nucleotides in the Y-form structure. Jakobsen et al. 30 have further shown that sensing of the stem-loop structures of lentiviral ssDNA molecules, including sstDNA is dependent on IFI16 and STING. Beyond DNA recognition in the infected cells, there are now emerging evidence to support that cGAMP propagates signals to adjacent non-infected cells, hence spreading antiviral activity. First, it was reported that cGAMP can diffuse to neighboring cells through gap junctions to stimulate STING-dependent type I IFN expression. 45 Second, cGAMP has been shown to be packed in viral particles. Two papers by Bridgeman et al. and Gentili et al., 46, 47 detected cGAMP in Vaccinia virus and murine CMV virions as well as in lentivector-derived lentivirus particles. cGAMP-containing virus particles stimulated cGAS − / − STING +/+ cell lines to produce type I IFN and the particles were further able to activate dendritic cells. At present it is not known whether cGAMP is actively packed into the viral particles as an antiviral strategy to allow early type I IFN responses in infected cells and in cells with low cGAS expression, or whether cGAMP is randomly taken up together with cytosolic material as the virus particle maturates and are released from the host cell. A third possibility is that some viruses actively incorporate cGAMP, as low levels of type I IFN might influence the infection positively. Studies of MHV68 have shown the establishment of latency to be IFN dependent and IFN was furthermore shown important for the inhibition of acute cell damages resulting from uncontrolled virus replication. 48 EVASION OF DNA-STIMULATED IMMUNE RESPONSES BY HERPESVIRUSES As described above, the DNA sensing pathway is activated by DNA from different sources upon virus infection, but due to the co-evolution of viruses and mammalian cells, viruses have learned to counteract the innate immune system. Several viral evasion mechanisms resulting in the inhibition of type I IFN responses have been reported, which demonstrates the importance of this class of antiviral cytokines in defense against viruses.