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lular entry receptors for KSHV. Integrins are entry receptors utilized by KSHV in
adherent cells such as endothelial cells, fibroblasts, and monocytes [ 85 ]. DC-SIGN
is a dendritic cell specific entry receptor that is expressed on the DC cell surface and
is exploited by KSHV in human myeloid dendritic cells, macrophages, and B cells
during infection [ 86 ]. xCT is a fusion-entry receptor for KSHV infection in HMVEC
cells [ 87 ]. EphA2 is the entry receptor utilized by KSHV in HFFs [ 88 ]. The interac-
tion between KSHV glycoproteins and host cellular receptors not only promotes
viral entry but also triggers host cell signaling pathways that may modulate the cel-
lular microenvironment to enhance virus entry and infection.
During early infection, focal adhesion kinase (FAK) and Src are induced to facil-itate KSHV entry and infection. FAK is an important tyrosine kinase activated by
the KSHV-integrin interaction, inducing multiple biological processes including
cell adhesion, proliferation, migration, apoptosis, and endocytosis [ 89 ]. KSHV gly-
coprotein gB can phosphorylate FAK, leading to the assembly of a membrane-
bound signaling complex and linking other kinases to downstream signaling events,
facilitating KSHV entry [ 90 ]. Phosphorylated FAK associates with other kinases
such as Src and RhoA to facilitate KSHV entry and infection. Moreover, Src kinases
are also critical for the endocytosis of KSHV [ 91 ].
During early infection, phosphoinositide 3-kinase (PI3K) interacts with RhoA-GTP to assist KSHV entry and infection. PI3K is involved in KSHV entry as a sig-
nal mediator, which can be activated via the interaction between KSHV and the
cellular receptor EphA2. This results in signaling to downstream RhoA GTPases
and other effectors to promote endosome formation and endosome trafficking dur-
ing KSHV entry [ 92 ]. The RhoA GTPase pathway, which is induced by KSHV gB
through the FAK-Src-PI3K pathway, is a vital signaling pathway regulating endocy-
tosis of KSHV. Recent reports showed that reactive oxygen species (ROS) generated
by KSHV have a significant impact on the entry of KSHV by amplifying the initial
host signal including EphA2, FAK, Src, and Rho GTPase [ 93 ].
In conclusion, the coordinated activities of these proteins play an important rolein regulating the mechanism of KSHV entry and infection.
7.3.2 Intracellular Trafficking
KSHV enters the host cell cytosol and delivers its genome in infected cell nuclei as
early as 15 min postinfection, and trafficking of KSHV DNA to the nucleus is maxi-
mal at 90 min postinfection, suggesting that KSHV trafficking is a very rapid pro-
cess [ 94 ]. During KSHV infection, Rho GTPase is involved in microtubule
acetylation and aggregation, which can increase the nuclear delivery of the KSHV
genome. Moreover, Rho GTPase utilizes dynein proteins (Dia-2) to rearrange the
cytoskeleton, leading to acetylation and aggregation of microtubules. Rho GTPase
is activated by KSHV infection targeting the FAK-Src-PI3K signaling pathway
[ 94 ]. Therefore, KSHV infection-induced Rho GTPase plays an important role in
facilitating not only virus entry but also the nuclear delivery of viral DNA.
S. Li et al.