BY

ASIF IQBAL KHATTAK

e-mail: microbiologist119@gmail.com

M.Phil Microbiology

HEPATITIS C

MENU ITEMS

• Introduction.

• The hepatitis C virus.

• Morphology and physicochemical properties

• Genome and proteins

• Antigenicity

• Cause of disease

• Stability

• Diagnoses

• Host immune réponse

• Pathogenèses

• Prévention and Treatment

HEPATITIS C - AN INTRODUCTION

• Hepatitis is a general term meaning inflammation of the liver and can be caused by several mechanisms, including infectious agents.

• Viral hepatitis can be caused by a variety of different *viruses such as hepatitis A, B, C, D and E.

• Since the development of *jaundice is a characteristic feature of liver disease

and not just viral hepatitis.

• A correct diagnosis can only be made by testing patients’ *sera for the presence

• of specific anti-*viral *antibodies.

HCV - VIROLOGY• The Virus

• Single stranded, positive sense, RNA 9.6 kb .

• Hepacivirus Genus

• Falviviridae family.

• Icosahedral, enveloped.

• ~ 50 nm.

• Discovered in 1989.

DISCOVERY

• In 1989 the *virus responsible for most transfusion-associated non-A non-B hepatitis was identified and cloned, and named hepatitis C *virus (HCV).

• Hepatitis C is also called type C hepatitis, Parenterally transmitted non-A non-B hepatitis (PT-NANB), Non B transfusion-associated hepatitis, Post transfusion non-A non-B hepatitis, HC.

HCV - GENETICS• Six genotypes, 1 through 6

• Multiple subtypes, a, b, c, etc.

• Further divided into quasi species, varying in RNA sequence by 1-9%

• RNA sequence may vary by 35% between genotype

• Great genetic diversity.

• Most HCV cases in the Western world are the result of genotype 1 HCV, followed by genotypes 2 and 3. Genotypes 4 and 5 are found in Africa and genotype 6 occurs in Asia.

HCV RECEPTOR AND CELL LINE• CD81.

• scavenger receptor class B type I (SR-BI).

• mannose-binding lectins

• Huh-7

CAUSES THE DISEASE

• Hepatitis C is caused by infection with the hepatitis C *virus (HCV), an enveloped, single stranded, positive sense RNA *virus.

• The *virus infects liver cells and can cause severe inflammation of the liver with long-term complications.

• The onset of disease is usually insidious, with anorexia, vague abdominal discomfort, nausea and vomiting, fever and fatigue, progressing to *jaundice in about 25% of patients, less frequently than hepatitis B.

• Of those exposed to HCV, about 40% recover fully, but the remainder, whether they have symptoms or not, become chronic *carriers.

• Of these, 20% develop *cirrhosis. Of those with *cirrhosis, up to 20% develop liver cancer.

PROGRESSION OF LIVER DISEASE

HOW IS HCV SPREAD?

• Hepatitis C *virus is usually spread by sharing infected needles with a *carrier, from receiving infected blood, and from accidental exposure to infected blood.

• Some people acquire the infection through nonparenteral means that have not been fully defined, but include sexual transmission in persons with

• high risk behaviors, although transmission of HCV Is less common than that of HBV and HIV.

• HCV is not spread by breast feeding, sneezing, coughing, hugging, sharing eating utensils or drinking glasses, other normal social contact, food or water.

CONT.…

• Mother-to-baby transmission is now well documented, but uncommon.39 Needs a high viraemia (>1 log ) as found in HIV co-infection.

• A person who has hepatitis C can still get other types of hepatitis, such as hepatitis A or hepatitis B.

WHO IS SUSCEPTIBLE TO INFECTION?

• Susceptibility is general.

• Humans and chimpanzees are the only known species susceptible to infection, with both species developing similar disease

IMMUNE RESPONSE• All individuals mount an innate immune response to HCV infection.

• This can be seen as early as 2 days after infection and involves protein kinase R, interferon regulatory factors, and antiviral gene products, such as type I interferon-inducible genes and immune transcription factors .

• The role of antibodies in controlling HCV infection is unclear and has been poorly studied; antibodies are thought to play a minimal role, however, as the virus can be cleared in the absence of a detectable antibody response.

• In addition, most neutralizing antibodies target the E2 glycoprotein. The high variability in E2 would produce viral variants that could evade antibodies fairly easily.

WHERE IS HCV A PROBLEM GLOBALLY?

• HCV infections are common worldwide.

• It is estimated that about 3% of the world’s population have HCV.

• There are about 4 million *carriers in Europe alone.

WHEN IS HEPATITIS C CONTAGIOUS?

• HCV positive persons are those who:

- have anti-HCV antibodies in their blood, and/or

- have HCV RNA or HCV core antigen detected in their blood.

• All HCV positive persons are considered potentially infectious.

• Imprudent contact with their blood can lead to HCV infections.

• HCV positive persons should :

• not donate blood, body organs, tissue, or semen.

• not share toothbrushes or razors.

• keep cuts and skin lesions covered.

CONT..….• The presence of anti-HCV *antibodies cannot be confirmed until 12-27 weeks after

exposure creating a window period of seronegativity and potential infectivity.

• HCV RNA, as detected by *polymerase chain reaction (PCR) or HCV core antigen detection, becomes positive within days of inoculation.

• PCR has become the method of choice for early diagnosis, core antigen detection is currently under evaluation.

THERE ARE NO AVAILABLE VACCINES FOR HCV. WHY?

• Currently there is no *vaccination against hepatitis C.

• One reason being that the *virus comes in many forms and constantly mutates leading to “swarms” of closely related viral genomic sequences (referred to as quasi-species).

• But now a day a drug is discovered against Hcv that is “sovildi”.

THE HEPATITIS C VIRUS

• Although its means of transmission are well documented, the hepatitis C *virus itself still remains an enigma.

• The hepatitis C *virus is an enveloped RNA *virus with a diameter of about 50 nm, classified as a separate genus (Hepacivirus) within the Flaviviridae family.

• The *genomic organization and sequence of HCV resembles that of the pestiviruses and flaviviruses.

• The reservoir of HCV is man, but the *virus has been transmitted experimentally to chimpanzees.

DIAGNOSIS • LIVER BIOPSY

• ELIZA (serum antibody)

• PCR (nucleic acid)

• The *genome of HCV is highly mutable.

• Because HCV is an RNA *virus and lacks efficient proofreading

• ability as it replicates, *virions infecting humans undergo evolution with time, giving rise to the notion that HCV persists as a collection of *virus quasispecies.

• By constant mutation, HCV may be able to escape host immunologic detection and elimination.

• HCV undergoes rapid mutation in a hyper variable region of the *genome coding for the envelope *proteins and escapes immune surveillance by the host.

• As a consequence, most HCV-infected people develop chronic infection.

• HCV also knocks out the host’s Innate Immunity.

• Mutations are not randomly distributed along the *genome, but are most pronounced within a hyper variable region located near the N-terminus of E2.

• This region maps at a surface loop of the E2 *protein containing a B-cell *epitope that undergoes *antigenic evolution over time.

• HCV is highly heterogeneous.

• Eleven HCV *genotypes with several distinct subtypes have been identified throughout the world.

• These diversities have distinct consequences:

although different strains have not been shown to differ dramatically in their virulence or pathogenicity, different *genotypes vary in their responsiveness to *interferon/ribavirin combination therapy.

• . Moreover, such heterogeneity hinders the development of *vaccines, since *vaccine *antigens from multiple *serotypes will probably be necessary for global protection.

CURRENT THERAPY• Combination pegylated interferon-α and ribavirin (nucleoside).

• 50-80% effective.

• Cyclosporine A

Inhibits stimulation of genes essential for T cell activation

• Arsenic Trioxide

Inhibits HCV replication

HOW CAN HEPATITIS C BEPREVENTED?

• Although there is currently no vaccine to prevent hepatitis C, there are ways to reduce the risk of becoming infected with the Hepatitis C virus.

• Avoid sharing or reusing needles, syringes or any other equipment to prepare and inject drugs, steroids, hormones, or other substances.

• Do not use personal items that may have come into contact with an infected person’s blood, even in amounts too small to see, such as razors, nail clippers, toothbrushes, or glucose monitors.

• Do not get tattoos or body piercings from an unlicensed facility or in an informal setting.