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Immune Evasion Strategies of Hepatitis C Virus

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Immune Evasion Strategies of Hepatitis C Virus IMMUNE EVASION STRATEGIES OF HEPATITIS C VIRUS Master Thesis Masters Program Infection & Immunity Kevin Budding, 0470201 October 2010 Supervisor: Dr. Debbie van Baarle About the front cover: The picture is a fluorescence microscope image of a GFP (Green fluorescent protein) labeled HCV protein, which associates to lipid droplets (red). The lipid mechanism is important for HCV and the association gives an indication of that importance. Picture is courtesy of Mr. Torsten Schaller, Immunology & Molecular Pathology department, University College London, 15th April 2010 Reference: http://www.grad.ucl.ac.uk/comp/2006-2007/research/gallery/index.pht?entryID=126 1 OUTLINE 1. Introduction 3 2. Hepatitis C virus 4 2.1 Epidemiology 4 2.2 Hepatitis C pathogenesis 6 2.3 Genomic organization and protein function 6 2.4 Viral life cycle 9 3. The innate immune response against HCV and viral evasion 12 3.1 Pattern recognition and NS3/4A 12 3.2 Interferon-β signaling and viral evasion 14 3.3 Interferon stimulation genes and viral evasion 14 3.4 Natural killer cells and HCV 15 4. The adaptive immune response against HCV and viral evasion 17 4.1 The humoral immune response and viral evasion 17 4.2 The cellular immune response and dendritic cell dysfunction 17 4.3 T cell failure 20 4.4 Regulator T cells 21 4.5 T cell homing capacity 21 4.6 Immune evasion through viral mutations 22 5. Therapies and vaccination 24 5.1 Current and future therapies 24 5.2 Vaccine development 26 6. References 28 2 1. INTRODUCTION In this thesis I will discuss the “tug of war” between hepatitis C virus (HCV) and our innate and adaptive immune system. A chronic HCV infection is the leading causative agent for liver cirrhosis, and currently over 200 million people are infected worldwide. According to epidemiological studies, HCV infects around three till four million people per year. I will start with elaborating on the epidemiology and pathogenesis of the virus, followed by the viral characteristics of HCV, taxonomy, replication cycle, structure, and genome. The focus of this paper will be on the aspect of viral persistence. In order to understand the immune evasive strategies of HCV I have divided the immunological response in two different components, the innate and adaptive component. I have tried to integrate the type of immune response with the immune evasion strategies of HCV. In the therapy section of the thesis I will elaborate on the currently used treatments, their mechanisms of action, the possible potential for vaccine development, and the reaction of the virus on the various therapeutic compounds. With this thesis I have tried to give a coherent, comprehensive insight into the clinical relevance of an HCV infection, the viral characteristics, the immune responses against HCV and HCVs strategies to evade these, and initiate a persistent infection. Kevin Budding, October 2010 3 2. HEPATITIS C VIRUS 2.1 EPIDEMIOLOGY The hepatitis C virus (HCV) was discovered in 1989 via molecular cloning instead of virus purification1. The first signs of a different form of hepatitis (known as non-A, non-B hepatitis) were already present around the 1970s2. Data up to 2005 indicate that the seroprevalence (number of persons who test positive for a specific disease based on blood serum specimens) of HCV is 2%, accounting for 123 million people in the world, making it the major causative agent of chronic liver diseases worldwide3. Although the prevalence of HCV infection is rather high worldwide, there is geographical spreading Figure 1. Worldwide prevalence of HCV3. Seen in the seroprevalence of the virus (see figure 1). Although the figure depicted above shows quite a clear figure of HCV seroprevalence throughout the world, with the virus mostly present in both Africa and Asia and less in the developed world. It is very difficult to obtain the data and to interpret this. This is due to the fact that most studies are conducted within non-representative populations, such as blood donors or patients who already suffer from chronic liver disease. However, mathematical models have been used in developed countries to measure the seroprevalence of HCV. Via these models it is shown that in the USA there is an increasing 4 seroprevalence of HCV over the past decades, 0-44 per 100000 before 1965, increasing to 100-200 around the 1980s4. An Australian model based upon new HCV infections also shows a steady increase in new HCV cases over the past decades5. Although there seems to be a decline in newly acquired HCV infection in the 1990s, al mathematical models used for the prediction of HCV seroprevalence support the idea that this seroprevalence will rise in the coming decades. Transmission of HCV occurs via blood-to-blood contact. Important factors that contribute to this transmission are blood transfusions from unscreened donors, drug injections, and non-sterile therapeutical procedures. The most important factor contributing to HCV transmission in developed countries is the usage of injection drugs. However, in developing countries non-sterile usage of syringes in a therapeutic setting is the primary source of HCV transmission6. According to studies conducted in the USA the majority of HCV injections, 68%, is caused by injection drug usage7. An important difference between the transmission of HCV and other viruses spread via blood-to-blood contact is that fewer sharing partners are necessary for a successful transmission of the virus. Also, indirect drug sharing, usage of the same cooker and rinse water, can contribute to HCV transmission8. Non-sterile injections are the primary source of HCV transmission in the developing world. Often sterile syringes are not available, or the injections are supplied by medical staff that lacks the necessary training and/or education. Another factor contributing to the higher transmission rate in a therapeutic setting is that often medication is injected into the patient, whereas in the western world it would be supplied orally9. A terrible example of HCV transmission via therapeutic injections is the kala-azar (Leishmaniasis, a parasitic disease) treatment program in India. The HCV infection rate among multiple injected patients was up to 31.1%10. Another example is the parenteral therapy for schistosomiasis in Egypt. It is believed that the high seroprevalence in Egypt is due to contamination during this therapy program10. In order to tackle this contribution to HCV transmission in 3rd world countries the World Health Organization (WHO) has set up the SIGN program (Safe Injection Global Network). Within this network, governments, international health agencies, corporations, and individuals collaborate for safer therapeutic injections3. The last important factor contributing to HCV transmission is blood transfusion. In the western world the contribution of this factor can almost be neglected due to strict rules and regulations in the all-volunteer donor system. Blood of the donors is tested for multiple blood-borne viruses, including HCV. Figures in the USA show a drop of HCV infections acquired after blood transfusion from 91% to 4%11. However, in most of the countries in the developing world there are no centralized rules and regulations, and no nation-wide blood-testing program is available. According to figures from the WHO, 43% of the donated blood in third world countries is not screened for HCV infection3. It has always been believed that In contrast to other blood-born viruses sexual transmission of HCV hardly occurs12. A 5 recent study by van Laar et al. that focused on acute HCV in HIV-infected men shows that that there is a substantial increase in acute HCV infection in men who have sex with men (MSM) who denied injecting drug use. These findings give new insights into the discussion whether or not sexual contact plays a significant role on HCV transmission13. 2.2 HEPATITIS C PATHOGENESIS A persistent HCV infection can lead to serious clinical symptoms. When faced with a HCV infection, the majority of the patients will develop chronic liver diseases (50% - 80)14. Steatosis, increased fat content of the liver, is the first clinical symptom during a HCV infection. When developing steatosis the patient will be able to react less effectively to antiviral therapy, and is prone to develop liver fibrosis15. Both liver fibrosis and cirrhosis are common liver disorders following HCV infection. Different risk factors influence the development of liver fibrosis, which can eventually lead to liver cirrhosis. These risk factors are age, sex, alcohol intake, diabetes, and co-infection with other viruses. The morbidity and mortality of chronic HCV infection is related to progressive fibrosis and the development of cirrhosis16. Patients who suffer from chronic HCV infection are prone to develop different types of liver cancers such as hepatocellular carcinoma (HCC). HCC is the fifth most common cancer in the world17, and chronic infection with HCV accounts for 20% of all HCCs worldwide18 Also, chronic HCV infection seems to be a risk factor for the development of cholangiocarcinomas, carcinomas that originate from the extra-hepatic biliary tree and the intrahepatic bile ducts19. 2.3 GENOMIC ORGANIZATION AND PROTEIN FUNCTION The hepatitis C virus is an enveloped single stranded positive RNA (+ ssRNA) virus and it belongs to the family of Flaviviridae. The genome length is 9.7 kb20. There are six different genotypes. Each genotype is further divided into different subtypes (a, b, c, etc.). The different genotypes are differentiated according to worldwide distribution and sequence variation21. The genome consists of a single open reading frame (ORF) with 2 untranslated regions (UTR) on both sides. These regions are important for viral protein and RNA synthesis and the coordination of these two processes22. Since the genome does not have a 5’cap the internal ribosomal entry site (IRES) in the 5’UTR is essential for translation.
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