TY  - INPR
A1  - Hennig, Thomas
A1  - Prusty, Archana B.
A1  - Kaufer, Benedikt
A1  - Whisnant, Adam W.
A1  - Lodha, Manivel
A1  - Enders, Antje
A1  - Thomas, Julius
A1  - Kasimir, Francesca
A1  - Grothey, Arnhild
A1  - Herb, Stefanie
A1  - Jürges, Christopher
A1  - Meister, Gunter
A1  - Erhard, Florian
A1  - Dölken, Lars
A1  - Prusty, Bhupesh K.
T1  - Selective inhibition of microRNA processing by a herpesvirus-encoded microRNA triggers virus reactivation from latency
N2  - 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.
KW  - Herpesvirus
KW  - HHV-6
KW  - miRNA processing
KW  - miR-30
KW  - mitochondria
KW  - fusion and fission
KW  - type I interferon
KW  - latency
KW  - virus reactivation
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-267858
UR  - https://doi.org/10.21203/rs.3.rs-820696/v1
ET  - submitted version
ER  -