Beta and Gamma Human Herpesviruses: Agonistic and Antagonistic Interactions with the Host Immune System

Abstract

Viruses are the most abundant and diverse biological entities in the planet. Historically, our main interest in viruses has focused on their pathogenic role, recognized by pandemics that have decimated the world population. However, viral infections have also played a major role in the evolution of cellular organisms, both through interchanging of genes with novel functions and shaping the immune system. Examples abound of infections that seriously compromise the host integrity, but evidence of plant and insect viruses mutualistic relationships have recently surfaced in which infected hosts are better suited for survival, arguing that virus-host interactions are initially parasitic but become mutualistic over years of co-evolution. A similar mutual help scenario has emerged with commensal gut bacteria. EBV is a herpesvirus that shares more than a hundred million years of co-evolution with humans, today successfully infecting close to 100% of the adult world population. Infection is usually acquired early in childhood persisting for the host lifetime mostly without apparent clinical symptoms. Disturbance of this homeostasis is rare and results in several diseases, of which the best understood are infectious mononucleosis and several EBV-associated cancers. Less understood are recently found inborn errors of the immune system that result in primary immunodeficiencies with an increased predisposition almost exclusive to EBV-associated diseases. Puzzling to these scenarios of broken homeostasis is the co-existence of immunosuppression, inflammation, autoimmunity and cancer. Homologous to EBV, HCMV, HHV-6 and HHV-7 are herpesviruses that also latently infect most individuals. Several lines of evidence support a mutualistic equilibrium between HCMV/EBV and hosts, that when altered trigger diseases in which the immune system plays a critical role. Interestingly, these beta and gamma herpesviruses persistently infect all immune lineages and early precursor cells. In this review, we will discuss the evidence of the benefits that infection of immune cells with these herpesviruses brings to the host. Also, the circumstances in which this positive relationship is broken, predisposing the host to diseases characterized by an abnormal function of the host immune system.

Keywords: EBV; autoimmunity; herpesvirus; immunodeficiency; immunosuppression; inflammation; lymphoproliferation; mutualistic relationship.

Figure 1

Beta- and gamma-herpesvirus mutualistic relationship with human host. While a restricted B cell tropism is usually found in vivo for gamma-herpesviruses, a wide tropism is observed for beta-herpesviruses that includes CD34 positive early progenitors, T cells, NK cells, monocytes, macrophages and dendritic cells. In homeostatic conditions, the herpesvirus immunomodulatory mechanisms positively influence host immunity, cross-protecting against heterologous pathogens through NK cell arming, and perhaps also due to their capacity to increase the numbers of T and NK cells, plus bystander activation through increased levels of local and systemic cytokines. Viral immunomodulation also improves tumor immunosurveillance, protects against auto-immune/immunopathological diseases and cooperate with other homeostatic processes, such as epithelial cell turnover and repair. A primed state indicates a possible pre-activated form of the immune cells triggered by IFNγ or other cytokines. PMN, polymorphonuclear cells.

Figure 2

Herpesvirus immunomodulatory mechanisms. Immunomodulatory viral genes function at multiple levels: (1) antagonizing complement, (2) interfering with host cytokines and chemokines, (3) & (4) interfering with the pathogen-associated molecular pattern (PAMP) signaling pathways that lead to interferon activation or directly with the effects of interferons, (5) inhibiting maturation of myeloid lineages, (6) interfering with the activity of terminally differentiated myeloid cells, (7) interfering with expression or function of NK cell activating and inhibitory receptors, (8) blocking intrinsic and extrinsic mechanisms of cell apoptosis, (9) interfering with activation of T cells through inhibition of peptide processing or HLA/peptide molecules surface deposition or through direct mechanisms of T cell inactivation, (10) inducing B cell differentiation into long-lasting immunoprivileged memory B cells, and (11) interfering with humoral responses though expression of Fc receptor-like molecules. Other reported mechanisms not illustrated here include formation of regulatory populations and interference with the PD1/PDL1 and other immune regulatory checkpoint proteins. Viral orthologs of human cytokines/chemokine/receptors are denoted with the letter v. This figure does not pretend to be a complete review but to illustrate the wide spectrum of immunomodulatory mechanisms displayed by herpesviruses.

Figure 3

Inborn errors predisposing to EBV-morbidity by compromising NK and T cell cytotoxic activity. The schematic diagram highlights the cell surface receptors and signaling-pathway elements that are responsible to control infection for herpesviruses. Signaling proteins shown in blue are those involved in regulation of PLC-γ. Those shown in orange are implicated in regulation of metabolism. XIAP is the only signaling protein described hitherto implicated in regulation of apoptosis. SAP has been shown to influence cell-mediated cytotoxicity by promoting NK cell adhesion by an LFA-1-dependent mechanism. Cytosolic proteins regulating vesicular traffic of cytotoxic granules are indicated in white.

Figure 4

Routes of controlled and uncontrolled infection using EBV as example. In the (A) scenario, EBV has the capacity to induce B cell expansions through formation of germinal center-like reactions and lymphoblastoid-like cells (LCLs). At the end, ad hoc cytotoxic CD8 T and NK cell activities directed against the LCL-like cells forces EBV to downregulate viral expression, restricting infection to the memory B cell compartment in which a persistent infection is established. In the (B) scenario, inborn errors interfere with the cytotoxic activity (upper part), resulting in hyperactive CD8 T and NK cells still capable to secrete cytokines, such as IFNγ, TNFα, IL-6, and presumably many others, creating the inflammatory microenvironment responsible for macrophages hyperactivity, HLH and lymphoproliferation. On a collateral scenario (lower part of B), inborn errors that affect CD4 T cell function result in impaired T cell-B cell cooperation with diminished formation of terminally differentiated B cells and dysglobulinemia syndromes. Since EBV resides in memory B cells, we hypothesized that this condition unbalances the capacity of EBV to establish unharmful latent infections. In the (C) scenario, still unknown causes tip the balance toward disproportionate bystander activation, loss of tolerance, molecular mimicry, superantigen activation, immune senescence, and perhaps other undocumented mechanisms resulting in inflammatory/autoimmune diseases.