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inflammasome) undergoes autoactivation via proteolytic cleavage to generate active
caspase1. Caspase1 cleaves pro-IL1 and pro-IL18 into their mature forms, leading
to their secretion to induce inflammation. The pyrin subfamily includes another
member known as AIM2. AIM2 replaces the LRR domain with an HIN (H inver-
sion) domain that recognizes double-stranded DNA genomes and triggers caspase1
activation. KSHV blocks NLRs by mimicking the receptor, although it elicits domi-
nant negative activity. KSHV ORF63 functions as a viral homolog of NLRP1 lack-
ing the pyrin domain. ORF63 interacts with NLRP1 and blocks NLRP1/3 to interact
with PYCARD, hindering assembly of the inflammasome [ 201 ]. In addition to
AIM2, IFI16 is a member of the PYHIN subfamily that senses cytosolic dsDNA;
instead of escaping recognition, KSHV usurps IFI16 to maintain latency, which is
related to viral life cycle regulation [ 202 , 203 ].
7.5.3.3 KSHV and RLRs
RLRs have an RNA helicase-like domain that can bind viral RNA and two CARD
domains at the amino terminus. RLRs interact with the adaptor protein MAVS at the
mitochondrial membrane when bound to viral RNA and activate the NF-κB and
interferon pathways via IKK and IRF3, respectively. RIG-I/MAVS suppresses both
KSHV infection and reactivation, although the underlying mechanism is not com-
pletely understood [ 204 ]. The KSHV tegument protein ORF64 harbors deubiquiti-
nase (DUB) activity and suppresses K63-linked ubiquitination of RIG-I and RIG-I
activation [ 205 ], thus counteracting the RLR-induced antiviral interferon pathway.
7.5.3.4 KSHV and the Cytosolic DNA Sensor
Unlike the PYHIN proteins AIM2 and IFI16, which induce inflammasome activa-
tion, the cGAMP synthase (cGAS)/cyclic guanosine monophosphate-adenosine
monophosphate (cGAMP)/STING pathway mediates the activation of IRF3 and
type I interferon responses. KSHV vIRF1 blocks the interaction between STING
and TBK1, thereby inhibiting the phosphorylation of STING and concomitant acti-
vation [ 206 ]. Furthermore, an N-terminally truncated cytoplasmic isoform of LANA
forms a complex with cGAS via direct interaction, disturbing cGAS/cGAMP/
STING signaling. In addition, the KSHV tegument protein ORF52 has been reported
to antagonize host cGAS DNA sensing by directly inhibiting cGAS enzymatic
activity [ 207 ].
In summary, the proteins encoded by the KSHV genome inhibit the host innateimmune system by blocking PRRs and the related pathways or take advantage of the
host immunity to establish latency, which promotes KSHV-related disease progres-
sion (Fig. 7.4).
7 KSHV Epidemiology and Molecular Biology