Hepatitis C virus infection: A liaison a trois amongst the virus

[Guest guest]

Hepatitis C virus infection: A "liaison a trois" amongst the virus

Hepatitis C virus infection: A "liaison a trois" amongst the virus, the host, and chronic low-level inflammation for human survivalDownload Complete pdf hereJnl of HepatologyVincenzo BarnabaDepartimento of Medicina Interna, Sapienza Universita di Roma, Fondazione Cesalpino, Fondazione Cenci Bolognetti, ItalyReceived 28 February 2010; received in revised form 20 May 2010; accepted 9 June 2010. published online 02 July 2010.Uncorrected ProofABSTRACT: Herein, various ambiguous aspects of the immune system that render this complex biological network so highly flexible and able to defend the host from persisting infections such as that induced by the hepatitis C virus (HCV) are reviewed. This ambiguity stems mainly from the property of the immune system to be both protective and harmful.

Immunity cannot be fully protective without producing a certain degree of damage (acute hepatitis resulting in resolving HCV infection). In addition, the balance between protection and tissue damage is critical for the development of chronic HCV infection. The establishment of a state of chronic low-level inflammation is instrumental to limit liver immunopathology, to limit viral spread, and ultimately to ensure a long-lasting survival of the host. It is dictated by a fine equilibrium maintained by multiple immunologic mechanisms, including: sensory perception of innate immunity, virus-specific T and B cell functions, control of immune responses, and finally the balance between immunity and immunopathology that has principally evolved to favor the species survival.Abbreviations: HCV, hepatitis C virus, pDCs, plasmocytoid dendritic cells, cDCs, conventional dendritic cells, PRRs, pattern-recognition receptors, TLRs, toll-like receptors, NOD,

intracellular nuclear oligomerisation domain, PAMPs, pathogen-associated molecular patterns, LPS, lipopolysaccharide, IL, interleukin, TRIF, toll-IL-1 receptor domain-containing adaptor inducing IFN-ß, IFN, interferon, DAMPs, damage-associated molecular patterns, UTR, untraslated region, RIG-I, retinoid acid-inducible gene I, IPS-1, adapter molecule IFN-ß promoter stimulator protein 1, p, plasmocytoid, JAK, Janus kinases, E, envelope, NS, non-structural, c, conventional, CCR7, Cys-Cys chemokine receptor 7, TGF, transforming growth factor, Th, T helper, NK, natural killer, KIR, NK cell inhibitory receptor, PD-1, programmed death-1 receptor, TCR, T cell receptor, L, ligand, Treg, T regulatory, Foxp, forkhead box P, IPEX, immunodysregulation polyendocrinopathy enteropathy X-linked, SHPs, Src homology 2-containing tyrosine phosphatases, pSTAT-5, STAT-5 phosphorylationConclusionsThrough the different (non-mutually exclusive) mechanisms

illustrated above, the host survives for a long time in parallel with both the persistent HCV infection and a low-grade liver inflammation that can degenerate into liver failure after several decades. The ambiguous co-existence of virus and inflammation results in an advantage for the evolutionary process and hence for human species survival. If immune responses were invariantly strong and aggressive during a persistent infection such as HCV, they would be unable to eliminate that infection, because of its acquired capacity to escape or to subvert them. In such a situation, exuberant (but non-protective) responses would produce prompt irreversible tissue (hepatic failure) damage, leading to catastrophic epidemic infections. Considering this point of view, chronic (low-level) inflammatory diseases seem to represent a sort of safeguard for the human survival. We can assume that chronic inflammation may be defined as the "Yin and Yang" of the immune

system. On the one hand, it guarantees the long-term survival of human hosts despite pathogen persistence. On the other hand, the imbalance of the homeostatic mechanisms maintaining chronic inflammation may degenerate into severe "side-effects" (i.e., the development of either autoimmune diseases or tumours) in a minority of infected individuals. From an evolutionary point of view, the onset of autoimmune diseases or the development of some tumours might be the price to pay following the establishment of chronic inflammation. Indeed, a status of pre-existing chronic inflammation can contribute to the development of cancer, by the production of growth and angiogenic factors eventually promoting cancer-cell survival, implantation, and growth. In addition, chronic inflammation can affect the immune-surveillance directly via its own intrinsic mechanisms (i.e., expansion of Treg cells, T cell exhaustion, etc.), and indirectly by the incapacity to limit the

immunosuppressive effects of tumours. The production of soluble factors (i.e., pro-inflammatory or cell growth cytokines) that favor cell proliferation, generally needed for the immune system to defend the host efficaciously, can also facilitate the mitotic cycle of non-lymphoid cells. In the long run, this prolonged stimulation can induce, as in the case of liver cirrhosis by both HBV and HCV, necrosis, cell renewal, and even neoplastic transformation [84]. A further example in HCV infection, is the chronic stimulation of B lymphocytes that can induce the monoclonal expansion of anti-IgG antibodies, which are responsible for the formation of cryoglobulins, autoantibodies, or even the establishment of follicular B cell lymphomas [85].The immune system simultaneously expresses different strategies that are seemingly opposite but eventually result in an evolutionary advantage. On the one hand, the immune response contributes to species survival;

on the other hand it can lead to the sacrifice of single individuals. During the evolutionary process, selective pressure has led to the generation of multiple ambiguous mechanisms to help counteract aggressive infectious agents. Although this is obtained at the cost of severe side-effects (tumour development, autoimmune diseases) in some individuals, these side-effects are considered irrelevant in terms of the survival of the species.The challenge for scientists is to eliminate the side-effects that emerge in the chronic HCV-host relationship (i.e., cirrhosis, liver failure, HCC, autoimmunity, etc.), possibly via ad hoc modeling and production of new antiviral drugs, immuno-modulatory molecules, therapeutic antiviral antibodies, antiviral small interference (si)RNAs, systems restoring T cell exhaustion (by inhibiting PD-1, Treg cell function, IL-10, or TGF-ß, etc.), and new vaccination strategies.

See Full Article

http://Hepatitis Cnewdrugs.blogspot.com/2010/07/hepatitis-c-virus-infection-liaison.html