103
episome from generation to generation [ 105 , 106 ]. The C-terminal DNA-binding
domain of LANA interacts with the host TR sequences to initiate semiconservative
replication by recruiting the host cell origin recognition complex (ORC) and mini-
chromosome maintenance (MCM) proteins, whereas the N-terminal chromosomal
binding domain enhances this latent replication process [ 107 ]. LANA has also been
reported to bind to several viral promoters and suppress viral lytic gene transcrip-
tion to maintain the latent process. For example, LANA can inactivate the intracel-
lular domain of Notch (ICN), which mediates transactivation of ORF50/replication
and transcription activator (RTA) and interacts with RBP-Jk, located in the pro-
moter of RTA, to repress the function of RTA, thereby preventing lytic reactivation
[ 108 ]. In addition to maintaining the KSHV latent genome, LANA also binds and
interacts with multiple cellular proteins, such as the tumor suppressors Rb and p53
to partly inactivate their functions [ 109 ]. Meanwhile, LANA can impact host gene
expression by interacting with certain transcription factors including ATF4/CREB2
and CPB [ 110 ]. In conclusion, LANA is a multifunctional protein that plays a cen-
tral role in the establishment and maintenance of viral latency.
v-Cyclin, the product of ORF72, shares 54% homology and 32% identity with
cellular cyclin D2, which binds and activates cellular cyclin-dependent kinase 6
(CDK6) to regulate cell cycle progression and proliferation [ 111 , 112 ]. v-Cyclin
forms a complex with CDK6 to mediate Rb phosphorylation and activation of p27
and histone H1 [ 113 ]. Although the exact role of this viral protein in the regulation
of KSHV latency is not fully understood, studies indicate that v-cyclin can interact
with CDK6, and the v-cyclin-CDK6 complex participates in mediating the
phosphorylation of nucleophosmin (NPM), promoting the interaction between
NPM and LANA and the recruitment of HDAC1 to maintain KSHV latency [ 114 ].
In addition, v-cyclin might induce apoptosis through the inactivation of the anti-
apoptotic factor BCL2, and the expression of v-cyclin is low during latency, which
prevents KSHV- triggered apoptosis [ 115 , 116 ]. In a similar functional relationship
to that of murine gammaherpesvirus 68 (MHV68) v-cyclin, KSHV v-cyclin modu-
lates the latent- lytic switch [ 117 ].
ORF71/vFLIP, also referred to as K13, is homologous with cellular FLICE [Fas-
associated death domain (FADD)-like interleukin-1 beta-converting enzyme, now
called caspase-8] [ 118 , 119 ]. vFLIP activates the NF-κB pathway through two
approaches: direct upregulation of the antiapoptotic transcription factor NF-κB and
binding to the inhibitor of NEMO (also referred to as IKK-gamma) [ 120 , 121 ].
NF-κB activation can hinder lytic gene expression, whereas NF-κB inactivation can
induce lytic reactivation. Therefore, vFLIP plays a critical role in maintaining
KSHV latency and promoting cell proliferation and survival [ 122 ]. Moreover,
vFLIP can also activate the JNK signal pathway by binding to RIP and TRAF2
upstream of IKK [ 123 ].
Kaposin, also known as K12, is composed of at least three proteins named
kaposin A, B, and C, which show differential translation initiation [ 104 ]. Kaposin
A is located in intracellular membranes and the plasma membrane and has the
potential to transform rodent fibroblasts, and the resulting cell lines form tumors in
nude mice. Kaposin B is a small soluble nuclear protein that can bind and activate
7 KSHV Epidemiology and Molecular Biology