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MAP kinase-associated protein kinase 2 (MK2) and the upstream kinase, p38

MAP kinase [ 124 ].

miRNAs are 21–23 nucleotide long RNAs that regulate gene expression through

base pairing to their mRNA targets. KSHV encodes 13 pre-miRNAs designated as

miR-K1 to miR-K12, which generate 25 mature miRNAs that are highly conserved

and expressed in all latently infected cells of KS and PEL [ 37 , 125 , 126 ]. Several

putative functions for KSHV miRNAs have been proposed since their discovery

[ 127 – 129 ]. Deletion of most KSHV miRNAs stimulates KSHV reactivation, sug-

gesting that these miRNAs play an important role in maintaining KSHV latent

infection. miR-K1 represses the activation of lytic viral promoters, miR-K12-7-5p

target viral ORF50 to stabilize latency [ 130 ], and miR-K10 inhibits cell apoptosis

by hindering pro-inflammatory responses [ 131 ]. Similar to cellular miRNAs, these

KSHV-encoded miRNAs have an impact on the development of viral malignancies

by affecting the differentiation status of the KSHV-infected cell [ 132 ]. Because

miRNAs are expressed in latency, they may promote cell survival and regulate

oncogenesis and the aberrant angiogenesis phenotype of KS [ 133 , 134 ].

7.4.2 Lytic Phase and Lytic-Associated Proteins

At 12 h postinfection, KSHV-infected cells display both latent and lytic gene expres-

sion. At approximately 24–48 h postinfection, KSHV-infected cells predominantly

express viral latent genes, except for a small fraction (1–3%) of cells that enter the

lytic replication phase [ 135 ]. However, latently infected cells have the potential to

undergo lytic reactivation, a process that can turn the virus from latency back into

lytic replication mode under different exogenous stimuli. The process of lytic reac-

tivation predominantly involves lytic DNA replication and infectious virion particle

production. Similar to other herpesviruses, during lytic reactivation, the entire viral

genome is expressed in a temporally regulated mode, resulting in the transcriptional

activation of three classes of lytic genes named immediate early (IE) genes, early

(E) genes, and late (L) genes [ 136 , 137 ]. Proteins encoded by the three classes of

lytic genes assist in the assembly and release of infectious as well as mature virion

particles that egress out of the cell by destroying the cellular membrane [ 100 ].

The IE genes consist of ORF50/RTA, ORF45, K8alpha, K8.2, K4.2, K4.1, K4,

ORF48, ORF29b, K3, and ORF70, and they are primarily expressed within 10 h of

induction. The proteins encoded by the IE genes are involved in gene transcription

and cellular modifications for the purpose of viral replication [ 138 ]. The E genes,

including K8, K5, K2, K12, ORF6, ORF57, ORF74, K9, ORF59, ORF37, K1,

K8.1A, ORF21, K2/vIL6, PAN RNA, vIRF1, and ORF65, are expressed between

10 and 24 h post-induction and encode proteins primarily required for DNA replica-

tion and gene expression [ 139 ]. The L genes, which are expressed after 48 h post-

induction, encode viral structural proteins such as membrane glycoproteins (gB and

K8.1) and a small viral capsid protein involved in the process of assembly and matu-

ration of the virion particles [ 140 ].

S. Li et al.