A viral miRNA disrupts mitochondrial architecture, suppresses type I interferon production, is necessary for productive infection and for virus reactivation, all by inhibiting multiple members of the host miR-30 family—creating a therapeutic target to suppress reactivation.
The mechanisms by which herpesviruses achieve latency, and reactivate from latency, have long been of great interest. Like the cells of its hosts, HHV-6A can produce microRNAs (miRNAs). A new study by Bhupesh Prusty and colleagues at the University of Wurzburg, published in Nature, finds that the virus-encoded miR-aU14 selectively inhibits the processing of multiple members of the host miR-030 family.
The viral miRNA interacts directly with the primary-miRNA hairpin loops of those host miRNAs. This interaction induces mitochondrial fission and leads to a marked disruption of mitochondrial architecture in the host cells, by activating the miR-30-p53-DRP1 axis. The mitochondrial disruption, in turn, impairs the production of type I interferons. This is followed by reactivation of latent HHV-6A.
To see whether the viral miRNA, miR-aU14, played a central role in triggering reactivation of latent HHV-6A, the investigators transfected cells harboring latent HHV-6A infection with synthetic miR-aU14 or with two mutants of this miRNA: the synthetic miR-aU14, but not the mutants, triggered reactivation, increasing the number of productively infected cells with the wild-type virus by a factor of 2.5-fold. This reactivation occurred in the absence of trichostatin-A (TSA), was augmented in the presence of TSA, and was greater with miR-aU14 alone than with TSA alone.
Thus, a miRNA encoded by HHV-6A (miR-aU14) regulates host miRNA processing in way that facilitates reactivation from latency and productive lytic infection. The virally-encoded miRNA constitutes an important lytic-latent switch; the virus can trigger its own awakening. Synthetic mimics of the HHV-6A miRNA can produce the same effects.
Important questions are raised by this valuable in vitro study: 1) Is this viral miRNA (miR-aU14) the primary mechanism by which the virus reactivates from latency, in vivo? If so, what signals the expression of the viral miRNA? 2) Through its disruption of mitochondrial architecture, could infection with HHV-6A significantly affect the ability of an infected organism to manufacture sufficient ATP, and significantly impair an organism’s immune response? 3) Could the viral miRNA be targeted as a means of suppressing both reactivation and productive lytic infection, such as by antisense antagomiRs? 4) Might similar miRNAs (or even this one) also be a lytic-latent switch in other human herpesviruses—including but not limited to HHV-6B? 5) Might other HHV-6A miRNAs affect host cell miRNAs similarly and, in doing so, contribute to human disease? 6) If HHV-6A achieves latency typically by integrating into the host cell telomere, how does this viral miRNA affect reactivation from its integrated state? 7) How different is the effect of this miRNA when HHV-6A infects different cell types, and what mechanisms may explain those differences? Finally, and most fundamentally, might miRNA-on-miRNA interactions (whether involving host or infectious miRNAs), such as this one, play an important but currently unrecognized role in human physiology and pathophysiology?
Read the full article: Hennig 2022