Tuning the Orchestra: HCMV vs. Innate Immunity

Abstract

Understanding how the innate immune system keeps human cytomegalovirus (HCMV) in check has recently become a critical issue in light of the global clinical burden of HCMV infection in newborns and immunodeficient patients. Innate immunity constitutes the first line of host defense against HCMV as it involves a complex array of cooperating effectors - e.g., inflammatory cytokines, type I interferon (IFN-I), natural killer (NK) cells, professional antigen-presenting cells (APCs) and phagocytes - all capable of disrupting HCMV replication. These factors are known to trigger a highly efficient adaptive immune response, where cellular restriction factors (RFs) play a major gatekeeping role. Unlike other innate immunity components, RFs are constitutively expressed in many cell types, ready to act before pathogen exposure. Nonetheless, the existence of a positive regulatory feedback loop between RFs and IFNs is clear evidence of an intimate cooperation between intrinsic and innate immunity. In the course of virus-host coevolution, HCMV has, however, learned how to manipulate the functions of multiple cellular players of the host innate immune response to achieve latency and persistence. Thus, HCMV acts like an orchestra conductor able to piece together and rearrange parts of a musical score (i.e., innate immunity) to obtain the best live performance (i.e., viral fitness). It is therefore unquestionable that innovative therapeutic solutions able to prevent HCMV immune evasion in congenitally infected infants and immunocompromised individuals are urgently needed. Here, we provide an up-to-date review of the mechanisms regulating the interplay between HCMV and innate immunity, focusing on the various strategies of immune escape evolved by this virus to gain a fitness advantage.

Keywords: NK cells; antigen presenting cell (APC); apoptosis; human cytomegalovirus; innate immunity; interferon system; restriction factors.

FIGURE 1

Outline of the HCMV strategies to evade from the interferon (IFN)-associated antiviral activity.

FIGURE 2

Schematic representation of the restriction activities played by the major RFs to impair HCMV replication.

FIGURE 3

Simplified model depicting the interplay among APCs during HCMV infection.

FIGURE 4

Schematic illustration of the strategies used by HCMV to modulate NK cell receptor ligands. The viral proteins mainly involved are depicted in a representative infected cell (right, color outlines), and activating (green) or inhibitory (red) signals relative to specific receptors on a NK cell (left) are shown.

FIGURE 5

Overview of the main apoptotic pathways and evasion strategies employed by HCMV.