Interplay between Human Cytomegalovirus and Intrinsic/Innate Host Responses: A Complex Bidirectional Relationship
Figure 3
Cells of innate immunity, activation and virus counterattack. (a) HCMV reactivates from latency in infected monocytes by inflammation or cellular differentiation, in which IL-6 and ERK/MAPK signaling are involved. Differentiated macrophages (Mφ) and dendritic cells (DC) are permissive for viral replication and, once infected, release proinflammatory factors. HCMV hampers the ability of Mφ and DC to properly differentiate from monocytes and present antigens to T lymphocytes by downregulating surface expression of CD1 and HLA class II molecules. DC-induced T-cell proliferation also decreases through mechanisms that involve virally encoded IL-10 and pUL18. IL-6, interleukin-6; TNF-α, tumor necrosis factor-α; MIF, macrophage migration inhibitory factor; MIP-1α, macrophage inflammatory protein-1α; MIP-1β, macrophage inflammatory protein-1β. +; upregulation or activation, −; downmodulation or inhibition. (b) HCMV-encoded proteins modulate NK-cell recognition of infected cells. pUL40 binds to HLA-E and upregulates its surface expression, potentiating its interaction with the inhibitory receptor CD94/NKG2A. pUL18, an HLA-I viral homolog, binds to the inhibitory receptor LIR-1. Expression of the ligands of the activating receptor NKG2D is inhibited by pUL16 (which targets MICB, ULBP1, and ULBP2) and pUL142 (targeting MICA and ULBP3). pUL141 prevents the expression of CD112 and CD155, ligands of the activating receptors CD226 and CD96, whereas pp65 interferes with the signal transduction of the activating receptor NKp30. Solid lines: possible interactions resulting in NK-cell inhibition. Dotted lines: impairment of interactions between activating receptors and their ligands.
