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Review
. 2021 Jul 13;22(14):7503.
doi: 10.3390/ijms22147503.

Evasion of the Host Immune Response by Betaherpesviruses

Daniel G Sausen  1 , Kirstin M Reed  1 , Maimoona S Bhutta  1 , Elisa S Gallo  2 , Ronen Borenstein  1
Affiliations
Review

Evasion of the Host Immune Response by Betaherpesviruses

Daniel G Sausen et al. Int J Mol Sci. .

Abstract

The human immune system boasts a diverse array of strategies for recognizing and eradicating invading pathogens. Human betaherpesviruses, a highly prevalent subfamily of viruses, include human cytomegalovirus (HCMV), human herpesvirus (HHV) 6A, HHV-6B, and HHV-7. These viruses have evolved numerous mechanisms for evading the host response. In this review, we will highlight the complex interplay between betaherpesviruses and the human immune response, focusing on protein function. We will explore methods by which the immune system first responds to betaherpesvirus infection as well as mechanisms by which viruses subvert normal cellular functions to evade the immune system and facilitate viral latency, persistence, and reactivation. Lastly, we will briefly discuss recent advances in vaccine technology targeting betaherpesviruses. This review aims to further elucidate the dynamic interactions between betaherpesviruses and the human immune system.

Keywords: HCMV; HHV-6A; HHV-6B; HHV-7; betaherpesvirus; immune evasion; immune response; viral evasion.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Pathogen Sensing, Interferon (IFN), and the JAK-STAT Pathway. Pathogen invasion triggers several pattern recognition receptors (PRRs), including NOD-like receptors (NLRs), RIG-I -like receptors (RIG-I), cGAS, and TLRs (toll-like receptors). These PRRs activate signal transduction pathways that culminate in the production of transcription factors and interferon regulatory factors, which in turn leads to the production of antimicrobial peptides, proinflammatory cytokines, chemokines, and type I IFN. Type I IFN then binds to the interferon α receptor (IFNAR), which phosphorylates JAK. Phosphorylated JAK recruits STAT, which is then phosphorylated, dimerizes, and translocates to the nucleus. Once in the nucleus, STAT upregulates the transcription of ISGs. The HCMV protein pUL145 inhibits STAT, while HHV-6B has been shown to upregulate STAT. The HCMV protein UL26 inhibits ISGs and ISGylation.
Figure 2
Figure 2
The cGAS-cGAMP-STING Pathway and Human Cytomegalovirus Immunoevasive Methods. The cGAS-cGAMP-STING pathway is activated after cGAS detects abnormal double-stranded DNA in the cytosol. cGAS produces cGAMP, which stimulates the translocation of STING to the golgi, where it oligomerizes. STING recruits TBK1, which then autophosphorylates and phosphorylates STING. STING recruits IRF3 to create a STING/TBK1/IRF3 complex. TBK1 then phosphorylates IRF3, which dissociates from the complex, dimerizes, and translocates to the nucleus. Once there, it stimulates interferon transcription. UL42 inhibits cGAS and promotes TRAPβ degradation via lysosomes. UL94 inhibits STING dimerization and prevents STING from recruiting TBK1. UL35 inhibits TBK1. IE86 facilitates the proteasomal degradation of STING.
Figure 3
Figure 3
Toll-Like Receptor (TLR) Signaling and Inhibition. The TLR signaling pathway begins after a pathogen-associated molecular pattern (PAMP) binds to the TLR. There are two main signaling pathways activated by TLRs. TLR activation through MyD88 results in the formation of a myddosome, which includes MyD88, IRAK1, IRAK2, and IRAK4. The myddosome then activates TRAF6, which activates TAK1. TAK1 phosphorylates the IKK complex, which in turn phosphorylates IκB. IκB phosphorylation triggers its proteasomal degradation and the subsequent release of the transcription factor NF-κB. The second pathway involves TRIF associating with the TLR. TRIF activates TRAF3, which activates TBK1 and IKKi. These phosphorylate IRF3. As in the STING pathway, IRF3 dimerizes and translocates to the nucleus to induce an interferon response. The HCMV protein US7 inhibits signaling by targeting TLR3 and TLR4 for proteasomal degradation, while the HCMV protein US8 inhibits signaling by destabilizing TLR3 and TLR4. Of note, HHV-6A and HHV-6B have been shown to downregulate TLR9 protein levels.
Figure 4
Figure 4
AKT and Apoptosis. There are two apoptotic pathways: extrinsic and intrinsic. The extrinsic pathway begins when ligands such as FAS ligand (FASL) or TRAIL bind their corresponding cellular receptors. The adaptor protein FADD is recruited to the receptor. FADD recruits procaspases to create the death-inducing signaling complex (DISC). Once DISC has formed, it facilitates autoproteolytic cleavage and caspase activation. Activated caspases cleave target molecules and stimulate apoptosis. The intrinsic pathway is initiated when the cell is exposed to stressors. The pro-apoptotic proteins BAK and BAX dissociate from BCL2 and disrupt the mitochondrial membrane, resulting in release of mitochondrial contents and apoptosis. The AKT pathway, which can be initiated through either EGFR or integrin stimulation, begins with receptor-mediated activation of PI3K. PI3K activation results in the formation of PIP3, which activates PDK1, which in turn activates AKT. AKT activates mTOR, which promotes cell survival. The human cytomegalovirus (HCMV) protein pUL7 and HCMV miRNAs inhibit FOXO. HCMV gB interacts with the EGFR while gH interacts with integrins to stimulate AKT.
Figure 5
Figure 5
Summary of Key Pathways and Associated Immunoevasive Methods. The immune response to betaherpesviruses begins with the detection of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs), including cGAS and toll-like receptors (TLRs). The cGAS/cGAMP/STING signaling axis results in the production of interferon (IFN) while TLRs can generate both IFN and other defensive compounds. IFN results in STAT activation, which stimulates production of interferon-stimulated genes (ISGs). Betaherpesvirus manipulation of cell survival is an integral element in their success as pathogens. Apoptosis may be stimulated by either intrinsic (BAK/BAX mediated mitochondrial perforation) or extrinsic (FAS ligand/CD95 binding, TRAIL/TRAILR binding) signals. The PI3K/AKT/mTOR signaling pathway represents a major pro-survival cascade. Immunoevasive methods are listed below.
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