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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