Innate immunity in the immunopathogenesis of chronic viral infection

Abstract

Natural killer (NK) cells have a key role in control and clearance of viral infections. To carry out this function NK cells are capable of recognising infected cells and responding with induction of apoptosis in these cells, and production of pro-inflammatory cytokines. Target cells are recognised through various stress or infection related activating signals alongside ‘missing self’ recognition of down-regulation of human leukocyte antigen molecules. Additional stimulation for NK cells comes in the form of the type I interferon (IFN), IFN-α, which is released by infected cells and the immune system’s sentinels, the dendritic cells (DC). As well as stimulating NK cells, IFN-α induces an anti-viral state in cells through upregulation of expression of IFN-stimulated genes.

Infections with hepatitis B, C, and δ viruses (HBV, HCV, HDV) cause viral hepatitis and are major risk factors for developing liver fibrosis. Despite these infections causing similar clinical manifestations, and until recently treatment for all three utilising IFN-α, these three viruses differ greatly. Human immunodeficiency virus (HIV) is the causative agent of acquired immune deficiency syndrome (AIDS). This disease is characterised by loss of CD4 expressing cells resulting in a diminished immune system that leaves the host susceptible to opportunistic infections. HIV-1 is the cause of the AIDS pandemic, while HIV-2 associates with a slower disease progression.

Each of these viruses is able to cause chronic infection. Part of the pathology of chronic infection, particularly HIV infection, is persistent immune activation and microbial translocation. In attempting to clear the infection the immune system can become perpetually activated, a condition associated with immune dysfunction. During this phase the immune response can contribute to disease progression through off-target effects, or appear as exhausted and dysfunctional.

In this thesis I will show that the phenotype and function of NK cells are altered during infection, primarily dependent upon the stage of hepatitis infection irrespective of infecting virus. For HIV infections NK cell activation is dependent upon the level of viral replication. During IFN-α therapy for hepatitis infections there is an increase of the chronic inflammation and microbial translocation marker sCD14, while NK cell function is altered due to fluctuations in intracellular STAT signalling.