Infectious Agents Associated Cancers Epidemiology and Molecular Biology

99

7.3 KSHV Life Cycle

KSHV can successfully infect multiple cells including endothelial cells, B cells,

monocytes, epithelial cells, and keratinocytes to establish latency [ 71 ]. KSHV can

also infect human and mouse fibroblast cells, owl monkey kidney cells, BHK-21

(baby hamster kidney) cells, and CHO (Chinese hamster ovary) cells [ 73 , 74 ].

However, KSHV does not infect rodents in vivo, and there are no small or primate

animal models that can imitate human KSHV infection and pathogenesis. KSHV

infection includes three steps: (1) manipulation of the host signaling pathways to

enter and traffic in the cytoplasm of target cells; (2) delivery of the viral genome into

the nucleus; and (3) initiation of viral gene expression for successful de novo infec-

tion. KSHV entry is the fundamental as well as key process for de novo infection.

7.3.1 Virus Entry

KSHV entry is a complex multistep process involving viral envelope glycoproteins

as well as a variety of cell surface molecules that are utilized by KSHV for its bind-

ing and entry.

Because KSHV displays a broad cell tropism, KSHV uses a cell type-specific

approach for entry [ 75 ]. For example, KSHV enters human B cells, fibroblasts,

epithelial cells, and endothelial cells by endocytosis. Specifically, KSHV enters

human dermal microvascular endothelial cells (HMVEC-D) and human foreskin

fibroblasts (HFFs) by macropinocytosis and clathrin-mediated endocytosis, respec-

tively [ 76 – 80 ]. Macropinocytosis, a specific form of endocytosis, is the major route

of KSHV infection in endothelial HMVEC and HUVEC cells. Clathrin-mediated

endocytosis is another major route involving the uptake of KSHV into the cell from

the surface via clathrin-coated vesicles.

KSHV entry is initiated by the binding of KSHV-encoded glycoproteins to

receptors in the host cell membrane. KSHV encodes several glycoproteins includ-

ing gB (ORF8), gH (ORF22), gL (ORF47), gM (ORF39), and gN (ORF53), which

are conserved among herpesviruses [ 81 , 82 ]. KSHV also encodes certain unique

lytic cycle-associated glycoproteins such as ORF4, gpK8.1A, gpK8.1B, K1, K14,

and K15, among which ORF4 and gpK8.1A are associated with the KSHV enve-

lope [ 16 , 17 , 83 ]. These glycoproteins are important for the following processes:

virus-host cell initial attachment, virus entry, viral particle assembly, and virus

egress. Among these glycoproteins, KSHV gB is the most vital envelope glycopro-

tein involved in the initiation of entry [ 84 ].

Similar to other herpesviruses, there are two categories of host cellular receptors

that can be recognized by KSHV glycoproteins. One is the host cellular binding

receptor heparan sulfate (HS), which promotes KSHV attachment and concentra-

tion in target cells [ 74 ]. The other one is the entry receptor that is highly specific

according to cellular tropism as well as the entry pathways utilized by

KSHV. Integrins, DC-SIGN, xCT, and ephrin receptor A2 (EphA2) are all host cel-

7 KSHV Epidemiology and Molecular Biology