TY  - JOUR
A1  - Sanyal, Anirban
A1  - Wallaschek, Nina
A1  - Glass, Mandy
A1  - Flamand, Louis
A1  - Wight, Darren J.
A1  - Kaufer, Benedikt B.
T1  - The ND10 Complex Represses Lytic Human Herpesvirus 6A Replication and Promotes Silencing of the Viral Genome
JF  - Viruses
N2  - Human herpesvirus 6A (HHV-6A) replicates in peripheral blood mononuclear cells (PBMCs) and various T-cell lines in vitro. Intriguingly, the virus can also establish latency in these cells, but it remains unknown what influences the decision between lytic replication and the latency of the virus. Incoming virus genomes are confronted with the nuclear domain 10 (ND10) complex as part of an intrinsic antiviral response. Most herpesviruses can efficiently subvert ND10, but its role in HHV-6A infection remains poorly understood. In this study, we investigated if the ND10 complex affects HHV-6A replication and contributes to the silencing of the virus genome during latency. We could demonstrate that ND10 complex was not dissociated upon infection, while the number of ND10 bodies was reduced in lytically infected cells. Virus replication was significantly enhanced upon knock down of the ND10 complex using shRNAs against its major constituents promyelocytic leukemia protein (PML), hDaxx, and Sp100. In addition, we could demonstrate that viral genes are more efficiently silenced in the presence of a functional ND10 complex. Our data thereby provides the first evidence that the cellular ND10 complex plays an important role in suppressing HHV-6A lytic replication and the silencing of the virus genome in latently infected cells.
KW  - human herpesvirus 6
KW  - ND10 complex
KW  - PML
KW  - lytic replication
KW  - latency
KW  - PML nuclear-bodies
KW  - gene-expression
KW  - virus-infection
KW  - in-vitro
KW  - DNA
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227337
VL  - 10
IS  - 8
ER  - 
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  -