Viral mechanisms for subversion of specific immune responses How viruses think?

Many viruses subvert particular parts of the immune system – synthesis of complement-regulatory molecules capture of cellular genes for cytokines or chemokines and their receptors the production of decoy proteins that mimic the host proteins involved in inflammation and immunosuppression – E.g. Decoy proteins for TIR domains that are part of the TLR/IL-1 receptor signaling pathway – The human cytomegalovirus (CMV ), another herpesvirus, produces a protein called UL18, which is homologous to an HLA class I molecule – CMV also impairs antiviral responses by producing a homolog of the cytokine IL-10, called cmviL-10, which down regulates the production of several pro-inflammatory cytokines by immune cells, including IFN, IL-12 and IL-23, IL-l, IL-6, and TNF-a, to promote tolerogenic rather than immunogenic adaptive responses to viral antigens Several viruses also produce molecules that interfere with chemokine responses, either by producing decoy chemokine receptors or chemokine homologs that interfere with natural ligand-induced signaling through chemokine receptors

Mechanisms used by viruses of the herpes and pox families to subvert the host immune system

Immune escape in HBV and HCV

HBV- Virus that sneak in the immune system HBV (DNA virus) uses three strategies to gently sneak in the immune system (innate immunity) – Viruses may remain undetectable for long periods of time i.e. can be two months elapse until a significant number of viruses are detectable – Mainly because HBV are not cytolytic, as death of infected cells is an important danger signal detected by the innate immune system – It does not activate the interferon defense system despite being an enveloped virus

Antibodies against HBsAg are detected until rather later during the infection They are usually soaked up by the empty viral envelopes The antibodies titre is an indication that the virus is cleared by immune system Due to the lack of neutralizing antibodies the viral clearance is largely dependent on the killer T cells In 70% of people infected the virus gets cleared by the immune system For the rest of 30% of infected individuals liver damage occurs as a result of the attack of CTL to hepatocytes resulting in symptoms such as – Elevated serum aminotransferases – Nausea – Vomiting – Liver pain – Jaundice – Dark urine These symptoms may continue for months until the virus gets cleared in 90% of infected people

HBV subverts the adaptive immune response by interfering with dendritic cell activation and maturation possibly myeloid DCs Consequently leading to the inadequate activation of CD4 T cells and a lack of TH1 cell differentiation The RNA polymerase that the virus uses to replicate its genome lacks proofreading capacity This contributes to a high viral mutation rate and thus a change in its antigenicity, which allows it to evade adaptive immunity

Damage due to the HBV- genotoxins Usually hepatocytes are in resting phase, therefore the damage caused by genotoxins is fixed before the damaged cells are replaced, p53 gene gaurds against any proliferation of any unchecked mutation However CTL-mediated killing of hepatocytes may lead to extra proliferation burden on liver cells due to which they may proliferate with mutated DNA In the presence of genotoxins and proliferation burden the liver cells may get exposed to cancer causing mutations Hep B associated liver cancers were found to contain cells having parts of HBV genomes HBV encoded protein i.e. X protein is known to play an important role in the pathogenesis towards liver diseases May disrupt the function of p53(tumor suppressor gene)- guardian of the genome Hepatocyte repair Hepatocyte regeneration

HCV- an escape artist RNA virus, identified in 1989 Infects both liver cells and macrophages Binds to low density lipoproteins (CD81) and infects the target cell 200 billion liver cells in adult human, infected hepatocytes may vary from % Immune response takes place through CTLs and antibodies As an envelped virus it is expected that interferon response will take place and eradicate it However two virally encoded proteins i.e NS5A and E2 seems to help virus escape the interferon response through inhibiting PKR Pathogenesis varies from genotype to genotype

Regulatory T cells play an important role in the pathogenesis of HBV and HCV infections

Regulatory T cells Play an important role in the outcome of infectious disease Some pathogens promote adaptive immune responses dominated by regulatory Treg cells rather than effector T cells Two kinds of regulatory T cells are present: – 'Natural' FoxP3+ Treg cells arise in the thymus and migrate to the periphery, where they help to maintain tolerance by suppressing the differentiation of lymphocytes recognizing autoantigens – 'induced' or 'adaptive' Treg cells- FoxP3+/- CD25+ CD4 regulatory T cells that differentiate from naive CD4+ T cells in the periphery

In most of the cases the induction of Treg cells is promoted by the pathogen, – which thus avoids clearance and can set up a chronic infection  This mechanism seems to contribute to chronic liver infections caused by HBV and HCV  Patients infected with HBV and HCV have elevated numbers of FoxP3+ Treg cells in the circulation and in the liver,  and in vitro depletion of Treg cells enhances cytotoxic lymphocyte responses against the virus  During infections with the protozoan parasite Leishmania major, Treg cells accumulate in the dermis, where they impair the ability of effector T cells to eliminate pathogens from this site However there are some studies that indicate the positive effects of Treg cells i.e. in restraining inflammation – studies in both humans and mice have shown that the inflammation occurring during ocular infections with HSV is limited by the presence of Treg cells – If Treg cells are depleted from mice before HSV infection, a more severe disease results, even when smaller doses of virus are used to cause infection – In the pulmonary disease that occurs in immunodeficient mice infected with the opportunistic yeast-like fungal pathogen Pneumocystis jirovecii (formerly known as Pneumocystis carinii), which is a common pathogen in immunodeficient humans Common chronic infection caused due to regulatory T cells