Virus-Encoded Control of Host Immune Responses by Herpesviruses

Introduction

Human herpesviruses are among the major causes of human viral diseases. Herpesviruses are double stranded DNA viruses that can cause latent infections in their hosts. The DNA genome is linear when in the virion, but it assumes a circular conformation once the virion gain entry into the nucleus. Herpesvirinea family consists of more than 100 members, but human beings are susceptible to eight members. The members of herpesviruses family are classified into three broad groups consisting of alpha, beta and gamma herpesvirinea2. The classification is based on biological features. Herpes viruses are enveloped, and their replication occurs in the host cell nucleus. The alpha herpesvirinea in humans includes Herpes Simplex 1 and 2 and Varicella Zoster virus. These viruses infect various cells and can cause latency in sensory ganglia.

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The beta herpesvirinea cause latency in secretory glands, lymphoreticular cells and other tissues like the kidney. The host range is a bit restricted and those which infect human include “Cytomegalovirus, Human Herpesviruses 6A and 6B, and Human Herpesvirus 7”.12 Gamma herpesvirinea viruses infective to man include Epstein-Barr virus and Human Herpes 8. Replication of these viruses occur in lymphoblastoid cells and target B or T lymphocytes. They establish latency in lymphoid tissues.2

After a primary infection, herpesviruses undergo a latent infection whereby the virus is inactive but can evade the host immune responses. In some situations, lytic replication can occur during the latent phases leading to a variety of diseases.1 This is the principal reason that makes herpesvirus infections difficult to treat. Herpesviruses have the ability to influence the host cell in a number of ways such as affecting protein synthesis, DNA replication, and immune responses. The ability to manipulate the host immunity is because the viruses have undergone co-evolution with the host, developing mechanisms to evade immune responses. The evasion mechanisms are achieved through various ways such as using encoded proteins to evade immune response, interference with host’s efficiency of identifying it, modulation of immune responses to their advantage.2

Control of host immune responses

Herpesviruses encode genes responsible for protein expression. The proteins are involved in establishing latency, manufacturing DNA and formation of structural proteins that are salient in the replication of the virus. The proteins are also involved in, “nucleic acid packaging, viral entry, capsid envelopment, for blocking or modifying host immune defenses, and transitions from latency to lytic growth”12. Viral encoded control of host immune responses by herpes viruses is achieved through different mechanisms such as inhibition of apoptosis, regulating cell surface major histocompatibility complex I expression and regulation of the interferon pathway.2

Inhibition of Humoral Responses

Antibody-dependent complement lysis is a significant process for killing infected cells. Herpes simplex virus and Epstein-Barr virus have different complement molecules like CD46, CD55 and CD59 which are homologs of complement proteins.5 These proteins differently influence the various stages in the complement cascade. Human cytomegalovirus lack complement homologs but have developed ways of inhibiting complement cascade. This virus can utilize host cellular proteins like CD55 and CD59, and integrate it into its envelope; hence helping in inhibiting complement activity by reducing the amount of C3 convertases.8 The virus, thus, evades complement lysis and in turn promotes replication of the virus. Some viruses have the ability to encode homologs of complement molecules. Once they secrete these homologs, complement activation, which is a non-specific immune response, is inhibited.13 As such, the virus particles avoid being neutralized. Herpes simplex virus 1 and 2 encode Fc receptors; therefore, when antibodies bind this receptor, the Fc dependent immune responses is blocked and complement and phagocytes remain inactivated.5

Interference with Interferon

Interferon (type I and II) help in protecting the cells from viral infection. Herpesviruses have been shown to prevent interferon dependent transcriptional responses and signal transduction1. Human cytomegalovirus has the ability to inhibit the activation of signal transducers and activators of transcription mechanism, thus decreasing the amounts of jakas kinase and p48. Human cytomegalovirus also uses proteasome in the inhibition of signal transcription and transduction pathway. Human cytomegalovirus expresses early gene products that interfere with interferon signaling. These gene products are, “the immediate early 1(IE1) protein and immediate early 2 protein”1 . IE1 adheres to signal transducers and activators of transcription, thereby limiting the ISG transcriptional activator from the ISG promoter. Human herpesvirus 8 can interfere with interferon-induced transcription through its interferon regulatory factor gene which acts as a homolog, hence repressing interferon mediated transcription.5

Herpes simplex viruses can also interfere with interferon in various ways. They possess an infected cell protein34.5 gene which they utilize in regulating phosphorylation. The gene facilitates the removal of phosphate from protein phosphatase I and adding it to eukaryotic translation initiation factor -2α (elF-2 α), hence reactivating it. Herpes simplex viruses, through unknown mechanisms, can produce 2’5’ oligoadenylate antagonists, thereby blocking the 2’5’ oligoadenylate synthetase system.5 Epstein-Barr viruses have EBNA-2 gene which they utilize in inhibiting signal transducers and activators of transcription pathways, thereby reducing the level of interferon induced transcription.6

Control of Host Immunity through Regulation of Cytokines and Cytokines

Cytokines are involved in the initiation of innate and adaptive immunity. Herpes viruses have developed mechanisms of controlling the production and activity of cytokines. Epstein-Barr virus can, for instance, through its latent membrane protein induce certain tumor necrosis factor receptor and CD 40 transduction mechanisms to behave like cytokine reactions, facilitating the proliferation of the virus in the cell.6 Herpesviruses can also mimic cytokines and cytokine receptors hence inhibiting cytokine activities. These viruses also have viral interleukin-6 and viral interleukin-17 which are cytokine homologs. The homologs have been shown to have an immunomodulatory function, in addition to being implicated in promoting the growth of cells that the viruses use for replication.9

Herpesviruses also appear to regulate the function of chemo-attractant cytokines involved in the mobilization of white blood cells to sites of infection.2 This is achieved by the ability to encode chemo-attractant cytokines or chemokines that act as antagonist hence preventing leukocyte mobilization, or to act as agonists hence promoting proliferation of cells that are essential in viral replication. The chemokines also play a role in inhibiting Th1 anti-viral reactions. When the open reading frame of human herpesvirus 8 is stimulated, it enhances cell growth; hence promoting viral replication.6 Human Cytomegalovirus and human herpesvirus 6 have also been shown to encode viral chemokine receptors that lower the level of T-cell expression, and transcription in tissue culture. This indicates the likelihood of inhibiting chemokine functioning locally. Epstein-Barr virus, through the expression of latent membrane protein-I gene, can mimic tumor necrosis factor receptor and CD 40 signaling channels.12 This, therefore, inhibits cytokine activity.

Inhibition of Apoptosis

Programmed cell death is often a normal host innate response to aimed at preventing viral propagation. However, some viruses encode proteins that regulate this process. These viral proteins are anti-apoptotic and usually target cellular molecules involved in the apoptosis process.

Viruses inhibit activation of caspases, encode homologs of the anti-apoptotic protein Bcl2, block apoptotic signals triggered by activation of tumor necrosis factor receptor family members by encoding death-effector-domain-containing proteins, and inactivate IFN-induced PKR and the tumor suppressor p53, both of which promote apoptosis.1

Human herpesvirus 8 have K13 gene that helps in the inhibition of the activation of caspases and programmed death cell stimulated by death receptors. The open reading frame 16 of this human herpesvirus 8 is also a homolog to the viral anti-apoptotic gene Bcl-2 which inhibits programmed cell death.4 Epstein-Barr virus also expresses 5HL gene which is a homolog of the anti-apoptotic protein Bcl-2. Herpes simplex viruses express gl protein which is a homology GADD34 gene involved in the control of cellular growth and cellular damage. Human Cytomegalovirus also has IE-1 and IE-2 proteins which play a role in preventing tumor necrosis factor dependent cell death. This virus also have UL37 gene which target the mitochondrion to inhibit cell death induced by death receptors.11

Interference with Major Histocompatibility Complex Function and Avoidance of Natural Killer

Antigen presentation is a key ingredient of the immune reactions. This in turn depends on human leukocyte antigen, also called major histocompatibility complex. Human leukocyte antigens occur on the cell surfaces and present cellular proteins to the immune system. Proteins presented by major histocompatibility complex class I molecules are mostly recognized by CD8+ T cells, while those presented by class II molecules are recognized by CD4+ T cells. In the presentation of antigens by the major histocompatibility complex class I, the proteins are obtained through proteasomal degradation of cytosol proteins, and then translocated to the endoplasmic reticulum.10 In case foreign particles are presented by these molecules the cytolytic CD8+ T cells are activated. Major histocompatibility complex class II peptides are generated from endogenous proteins entering the lysosomes.

Herpesviruses can interfere with antigen processing, thereby inhibiting peptide generation and translocation. These viruses use different mechanisms to modulate the development, assembly and transport of major histocompatibility molecules.3 As a result, these viruses downregulate these molecules. For human Cytomegalovirus, various genes are known to interfere with major histocompatibility complex pathways. These genes include, “tegument protein pp65, US2, US11, US3, US6, US10, and UL82”11. The tegument protein pp65 blocks the viral IE-1 from being presented. US2 and US11 transport major histocompatibility complex class I molecules quickly into the cytosol to undergo degradation. This helps in down-regulating these molecules. The US3 gene down-regulates major histocompatibility class II molecules while US6 gene interferes with the molecules transportation by blocking the transporter associated with antigen processing. US10 is thought to play a role in delaying intracellular transportation of class I molecules while gene UL82 which encodes pp2 is thought to block the trafficking of class I molecules between the endoplasmic reticulum and cis-Golgi. Interference with major histocompatibility complex molecules directly inhibits T-cell activation. Some proteins expressed by herpesviruses also limit natural killer cells. For instance, human Cytomegalovirus has ULI8 which mimics class I molecules which inhibits natural killer cell lysis.7

References

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