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The endosomal sorting complexes required for transport (ESCRT) proteins,

including ESCRT-0, -I, -II, and -III, function in a sequential manner to mediate

endosomal trafficking with the VPS4 ATPase. A recent study showed that the

ESCRT-I complex protein Tsg101 plays an important role during KSHV trafficking.

Small interfering RNA assays showed that Tsg101 does not affect KSHV entry but

dramatically reduces the delivery of the KSHV genome to the nucleus [ 95 , 96 ].

7.3.3 Viral and Host Gene Expression

To overcome the host cell restrictions on virus entry and viral gene expression,

KSHV induces robust expression of ERK1/2, nuclear factor κB (NF-κB), and

nuclear factor E2-related factor 2 (Nrf2) transcriptional factors early during de novo

infection by interacting with the cell surface receptors [ 97 ]. For example, Nrf2, as a

transcription factor involved in the establishment of de novo KSHV infection, is an

important host factor and plays a crucial role in viral gene expression. The inhibi-

tion or knockdown of Nrf2 with the chemical brusatol blocks viral gene expression

[ 96 , 98 ].

In conclusion, KSHV has evolved with a prominent survival strategy that reflects

the biological complexity of the virus and host interactions [ 97 , 99 ]. KSHV cell

entry involves a sequence of events: (1) macropinocytosis and clathrin-mediated

endocytosis facilitate the rapid entry of viral particles into different cell types, (2)

modulation of the various host cell functions to enable KSHV trafficking from the

cytoplasm into the nucleus, and (3) induction of cytoplasmic ERK1/2, NF-κB, and

Nrf2 transcription factors early during infection to initiate viral gene expression

soon after the entry of the viral genome into the nucleus (Fig. 7.1). These data pro-

vide crucial information for the design of future drugs that can efficiently inhibit the

entry of KSHV.

7.4 Two Different Phases of the KSHV Life Cycle

Similar to other human herpesviruses, KSHV has two different phases of infection

referred to as persistent latent infection and transient lytic reactivation, which are

distinguished by their viral gene expression patterns [ 100 ].

7.4.1 Latent Phase and Latent-Associated Proteins

During latent infection, viral gene expression is highly restricted to limit host

immune responses while promoting cell survival. The latent viral genome is repli-

cated as a circular episome within the nucleus through host cellular DNA

7 KSHV Epidemiology and Molecular Biology