Attack, parry and riposte: molecular fencing between the innate immune system and human herpesviruses

Abstract

Once individuals acquire one of the eight human-pathogenic herpesviruses, the upcoming relationship is predefined to last lifelong. Despite the fact that acute phases of herpesviral replication are usually confined and controlled by a concerted action of all branches of the healthy immune system, sterile immunity is never reached. To accomplish this, herpesviruses evolved the unique ability to outlast episodes of efficient immunity in a dormant state called latency and a remarkable array of immune antagonists which counteract most (if not all) relevant aspects of intrinsic, innate and adaptive immune responses. Certain psychological and physiological conditions (such as stress, immuno-suppression or pregnancy) predispose for viral reactivation which can lead to recurrent disease and virus spread. One important pillar of immunity is the innate immune system. The leading cytokines of the innate immune response are interferons (IFN). IFNs reinforce intrinsic immunity, induce a cell-intrinsic antiviral state and recruit and orchestrate adaptive immunity. Consistently, individuals lacking a functional IFN system suffer from otherwise harmless opportunists and live-attenuated vaccines. The selective pressure elicited by IFNs drove herpesviruses to evolve numerous IFN antagonistic gene products. A molecular in-depth understanding of (herpes-) viral IFN antagonists might allow the design of novel antiviral drugs which reconstitute IFN responses by blocking the antagonistic function and thereby help the host to help himself. Additionally, virus mutants lacking immune evasins constitute promising candidates for vaccine viruses. Here we summarize the current knowledge on IFN antagonistic strategies of the eight human herpesviruses and try to decipher common strategies.

Who’s Driving? Human Cytomegalovirus, Interferon, and NFκB Signaling

“…The list of cellular sensors that detect and are activated by HCMV binding and entry continues to expand, and includes the TLR2 (toll-like receptor) and CD14 receptors that interact with viral gB and gH [ 17 , 18 ] as well as the intracellular dsDNA sensors Z-DNA binding protein 1 (ZBP1) [ 19 ], TLR9 [ 20 ], and cGAS [ 20 ], all of which detect the presence of the viral genome in the host cell. Seemingly in response to these cellular defenses, HCMV has evolutionarily developed a suite of IFN countermeasures that occupy a significant portion of viral coding potential (summarized in Figure 1 and reviewed in [ 12 , 21 , 22 ]).…”

The Human Cytomegalovirus pUL145 Isoforms Act as Viral DDB1-Cullin-Associated Factors to Instruct Host Protein Degradation to Impede Innate Immunity

“…Nevertheless, clearance is never achieved since latent CMV genomes remain. To enable efficient viral replication despite the presence of host immune responses, CMVs evolved a remarkable array of antagonists targeting intrinsic, innate, and adaptive immunity (Hengel et al, 1998;Le-Trilling and Trilling, 2015;Loenen et al, 2001;Powers et al, 2008). One important pillar of the immune system is the interferon (IFN) response.…”

STAT2-Dependent Immune Responses Ensure Host Survival despite the Presence of a Potent Viral Antagonist

“…Cytomegaloviruses express numerous immune-evasive gene products targeting most aspects of intrinsic, innate, and adaptive immunity (e.g., see references 5 and 6 ). The focus of this study was the antithetic relationship between the interferon (IFN) system and virus-encoded IFN antagonists.…”