Early Events in Kaposi's Sarcoma-Associated Herpesvirus Infection of Target Cells

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV), the most recently identified member of the herpesvirus family, infects a variety of target cells in vitro and in vivo. This minireview surveys current information on the early events of KSHV infection, including virus-receptor interactions, involved envelope glycoproteins, mode of entry, intracellular trafficking, and initial viral and host gene expression programs. We describe data supporting the hypothesis that KSHV manipulates preexisting host cell signaling pathways to allow successful infection. The various signaling events triggered by infection, and their potential roles in the different stages of infection and disease pathogenesis, are summarized.

Kaposi’s sarcoma-associated herpesvirus interacts with EphrinA2 receptor to amplify signaling essential for productive infection

“…KSHV attachment to the HMVEC-d cell surface occurs via heparan sulfate (HS) followed by temporal interactions with integrins (α3β1, αVβ3, and αVβ5) and the transporter xCT molecule. KSHV binding to these molecules results in the induction of FAK, Src, PI3-K, Rho-GTPases, Dia-2, PKC-ζ, ERK1/2, and NF-κB signal molecules (3)(4)(5)(6)(7)(8). Our studies using chemical inhibitors, dominant negative proteins, or cells lacking these molecules have shown that FAK, Src, PI3-K, and RhoA activation is necessary for KSHV entry (3)(4)(5)(6)(7)(8).…”

“…Our studies using chemical inhibitors, dominant negative proteins, or cells lacking these molecules have shown that FAK, Src, PI3-K, and RhoA activation is necessary for KSHV entry (3)(4)(5)(6)(7)(8). Microtubule acetylation by RhoA-GTPase induces the Diaphanous-2 molecule that facilitates the transport of capsid toward the nucleus via dynein motors (3)(4)(5)(6)(7)(8). KSHV-induced ERK and NF-κB are essential for the initiation of viral gene expression.…”

“…KSHV uses endocytosis for its entry into human endothelial cells, fibroblasts, B cells, and monocytes and uses actin-dependent macropinocytosis to enter into human microvascular dermal endothelial (HMVEC-d) cells and umbilical vein endothelial (HUVEC) cells (3). KSHV entry into adherent target cells is a multistep complex process, involving various viral glycoproteins and multiple cell surface molecules, which overlaps with the induction of host preexisting signal molecules followed by entry into the cytoplasm, release of viral capsid, and transport toward the nucleus via dyneinmediated transport along the acetylated thickened bundles of microtubules (3).…”

“…KSHV binding to these molecules results in the induction of FAK, Src, PI3-K, Rho-GTPases, Dia-2, PKC-ζ, ERK1/2, and NF-κB signal molecules (3)(4)(5)(6)(7)(8). Our studies using chemical inhibitors, dominant negative proteins, or cells lacking these molecules have shown that FAK, Src, PI3-K, and RhoA activation is necessary for KSHV entry (3)(4)(5)(6)(7)(8). Microtubule acetylation by RhoA-GTPase induces the Diaphanous-2 molecule that facilitates the transport of capsid toward the nucleus via dynein motors (3)(4)(5)(6)(7)(8).…”

“…However, MβCD inhibits PI3K, RhoA, Dia-2, and NFκB activation; microtubule acetylation; nuclear delivery of viral DNA; and viral gene expression (3)(4)(5)(6)(7)(8)(9). Nuclear delivery of KSHV genomic DNA does not lead to lytic gene expression and progeny virus formation; instead, KSHV expresses its latent genes and establishes latency (3). Hence expression of latency-associated genes is used as an indicator of infection and to monitor the effects of inhibition of various molecules involved in infection.…”