Preprint to new paper from Prusty

Boba

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Selective inhibition of microRNA processing by a herpesvirus-encoded microRNA triggers virus reactivation from latency

https://www.researchsquare.com/article/rs-820696/v1

Abstract
Herpesviruses have mastered host cell modulation and immune evasion to augment productive infection, life-long latency and reactivation thereof 1,2. A long appreciated, yet elusively defined relationship exists between the lytic-latent switch and viral non-coding RNAs 3,4. Here, we identify miRNA-mediated inhibition of miRNA processing as a novel cellular mechanism that human herpesvirus 6A (HHV-6A) exploits to disrupt mitochondrial architecture, evade intrinsic host defense and drive the latent-lytic switch. We demonstrate that virus-encoded miR-aU14 selectively inhibits the processing of multiple miR-30 family members by direct interaction with the respective pri-miRNA hairpin loops. Subsequent loss of miR-30 and activation of miR-30/p53/Drp1 axis triggers a profound disruption of mitochondrial architecture, which impairs induction of type I interferons and is necessary for both productive infection and virus reactivation. Ectopic expression of miR-aU14 was sufficient to trigger virus reactivation from latency thereby identifying it as a readily drugable master regulator of the herpesvirus latent-lytic switch. Our results show that miRNA-mediated inhibition of miRNA processing represents a generalized cellular mechanism that can be exploited to selectively target individual members of miRNA families. We anticipate that targeting miR-aU14 provides exciting therapeutic options for preventing herpesvirus reactivations in HHV-6-associated disorders like myalgic encephalitis/chronic fatigue syndrome (ME/CFS) and Long-COVID
 

Pyrrhus

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Thanks so much, @Boba , for posting this (Hennig et al., 2021) pre-print, along with the full abstract! :thumbsup:

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Brief Summary:
  • Herpesviruses like HHV6 can exist inside a cell in at least two different states: an active (lytic) state and a latent state. Depending upon both cellular and extra-cellular conditions, the virus can decide to switch from its lytic state to its latent state, or from its latent state to its lytic state.
  • A cellular micro-RNA (miRNA) is a piece of RNA that a cell normally makes in order to suppress the production of a cellular protein.
  • The pre-print identifies a way in which a viral miRNA (called miR-aU14) suppresses processing of cellular miRNA's, including a family of cellular miRNA's called miR-30.
  • When the viral miRNA suppresses the cellular miRNA's, it "triggers a profound disruption of mitochondrial architecture."
  • When the viral miRNA suppresses the cellular miRNA's, it also impairs the interferon pathway, which is the most important pathway in the intracellular immune system.
  • When the intracellular immune system is compromised by impairing the interferon pathway, the HHV6 virus reactivates, switching from its latent state to its active (lytic) state.
  • The pre-print mentions that injecting the viral miRNA into a cell with a latent HHV6 infection causes the virus to reactivate, switching from its latent state to its active (lytic) state.
  • The authors suggest that finding some way to suppress the viral miRNA might help to prevent reactivation of latent HHV6 infections.