Hepatitis viruses

At least 6 viruses  HAV  HBV  HCV  HDV  HEV  HGV?

Hepatitis viruses Target organLIVER!! They differ greatly in:  Their structure  Mode of replication  Mode of transmission  Course of the disease they cause

Hepatitis viruses HAV & HBV Non-A, non-B hepatitis viruses  (C, G, E..) HDV, delta agent Other non-A, non-B viruses (HSV, CMV..)

Hepatitis viruses /hepatitis Liver damage  Icteric symptomes Jaundice Release of liver enzymes

Hepatitis Viruses Hepatitis A, which is sometimes known as infectious hepatitis, (1) is caused by a picornavirus, a ribonucleic acid (RNA) virus; (2) is spread by the fecal-oral route; (3) has an incubation period of approximately 1 month, after which icteric symptoms start abruptly; (4) does not cause chronic liver disease; and (5) rarely causes fatal disease.

Hepatitis A virus Cause infectious hepatitis Fecal-oral Consumption of contaminated water, shelfish, or other food rna rna Picornavirusenterovirus 72 Heparnavirusunique genome

Hepatitis A virus/ structure & replication Naked icosahedral capsid + sense, ssRNA genome ~7470 b more stable to acid and other treatments Capsid more stable to acid and other treatments than other picornaviruses One serotype!

Structure of hepatitis A virus

Hepatitis A virus/Pathogenesis Ingestionoropharynx epithelial lining of intestines parenchymal cells of the liver bilestool (shedding into the stoo oool) ~ “10 days before symptoms of jaundice”

Spread of HAV within the body

Hepatitis A virus/Pathogenesis Replicates without producing apparent cytopathic effects Antibody protection against reinfection is lifelong The liver pathology caused by HAV=HBV (indistinguishable) immunopathology, not virus-induced cytopathology HAV cannot initiate chronic infection

Hepatitis A virus/Epidemiology ~40 % of acute cases of hepatitis Most infected people are contagious before symptomsspreads readily 90 % of infected children, % of infected adultshave inapparent (but productive) infection Virus is in high concentrations in stool spread via the fecal-oral route

Hepatitis A virus/Epidemiology “spread via the fecal-oral route” Contaminated water Food Dirty hands “Virus is resistant to” Detergents Acid (pH of 1) 60 o C Fresh water, salt water

Hepatitis A virus/Epidemiology “spread via contaminated shellfish” “Clams, oysters, mussels” They concentrate the viral particles (In Shanghai, China, in 1988, people are infectedclams from a polluted river)

Hepatitis A virus/Epidemiology Seropositivity rate of adults in various countries: Sweden13% USA41-44% Yugoslavia97% Taiwan88% Turkey xx%: 70-90%

Hepatitis A virus/Clinical syndromes “Symptomes very similar to those caused by HBV; stem from immune-mediated damage to the liver” Usually asymptomatic in children; milder than adults Initial symptomes: fever, fatigue, nausea, loss of appetite, abdominal pain Jaundice in 2/3 of adults, only in 1 or 2/10 of children

Hepatitis A virus/Clinical syndromes 99% of timecomplete recovery 1-3/1000 fulminant hepatitis 80% mortality rate

Time cours e of HAV infect ion

Hepatitis A virus/Laboratory diagnosis Time course of the clinical symptomes Identification of a known infected source Specific serologic tests  anti-HAV IgM by ELISA or RIA

Hepatitis A virus/Treatment, Prevention & control Fecal-oral spread Prophylaxis  Immune serum globulin Before or early in the incubation period: 80-90% effective in preventing clinical illness Vaccine: killed HAV vaccine (FDA appr)  For use in children or adults at risk for infection

Hepatitis B virus Hepa dna Hepa dnaviruses Infect : liver, kidneys, pancreas Only humans and chimpanzees

Hepatitis B virus/Structure Small Envelopped DNA genome Several unusual properties:  Small (3200 bases) -circular-partly double- stranded DNA  Encodes a reverse transcriptase  Replicates through an RNA intermediate

Hepatitis B previously known as serum hepatitis, (1) is caused by a hepadnavirus with a deoxyribonucleic acid (DNA) genome; (2) is spread parenterally by blood or needles, by sexual contact, and perinatally; (3) has a median incubation period of approximately 3 months, after which icteric symptoms start insidiously; (4) is followed by chronic hepatitis in 5% to 10% of patients; and (5) is causally associated with primary hepatocellular carcinoma (PHC). More than one third of the world's population has been infected with HBV, resulting in 1 to 2 million deaths per year. The incidence of HBV is decreasing, however, especially in infants, because of the development and use of the HBV subunit vaccine.

Unique Features of Hepadnaviruses Virus has enveloped virion containing partially double-stranded, circular DNA genome. Replication is through a circular RNA intermediate. Virus encodes and carries a reverse transcriptase. Virus encodes several proteins (HBsAg [L, M, S]; HBe/HBc) that share genetic sequences but with different in-frame start codons. HBV has a strict tissue tropism to the liver. HBV-infected cells produce and release large amounts of HBsAg particles lacking DNA. The HBV genome can integrate into the host chromosome.

Hepatitis B virus/Structure Virion: Dane particule, 42nm in diameter  Unusually stable for an envelopped virus Resist treatment with :  ether,  a low pH,transmission  Freezing,  Moderate heating

Hepatitis B virus/Structure Virion: Dane particule, 42nm in diameter include:  a polymerase Reverse transcriptase activity Ribonuclease activity  HBcAg  HBsAg, 3 forms: L>M>S glycoproteins, contains “a” determinant (goup- specific), and “d” or “y” and “w” or “r”, type-specific determinants

HBsAg and HBeAg are secreted into the blood during viral replication. The detection of HBeAg is the best correlate to the presence of infectious virus. HBcAg not present in sera.

Hepatitis B virus/Replication “Unique!”  Replicates through an RNA intermediate and produces and releases antigenic decoy particules (They used a girl hitch-hiker as the decoy to get him to stop)

A circular positive-strand RNA intermediate is first synthesized by: cell’s DNA dependent RNA polymerase RNA-dependent DNA polymerase: a negative strand DNA is formed positive RNA degragated Positive strand DNA is initiated but stops when the genome and the core enveloped RESULT: partially double stranded DNA Hepatitis B virus

Hepatitis B virus/Pathogenesis&Immunity HBV can cause:  Acute or  Chronic,  Symptomatic or,  Asymptomatic disease...

Hepatitis B virus/Pathogenesis&Immunity “It’s determined by the person’s immune response to the infection”

Hepatitis B virus/Pathogenesis&Immunity HBsAg and HBeAg in the blood: ongoing active infection The major source of infectious virus is blood  Semen  Saliva  Milk  Vaginal & menstrual secretions  Amniotic fluid

Hepatitis B virus/Pathogenesis&Immunity The virus replicates in hepatocytes with minimal cytopathic effectinfection proceeds without causing liver damage or symptoms HBV genome integrate into hepatocyte chromatin & remain latent filamentous forms of HBsAg hepatocyte cytopathology

Hepatitis B virus/Pathogenesis&Immunity cell-mediated immunity and inflammation are responsible for causing the symptoms and effecting resolution of the HBV infection by eliminating the infected hepat  cyte “ cell-mediated immunity and inflammation are responsible for causing the symptoms and effecting resolution of the HBV infection by eliminating the infected hepat  cyte ” “antibody (vaccinated people) can protect against reinfection”  Large amount of HBsAg!!  Immune complexeshypersensitivity

Hepatitis B virus/Pathogenesis&Immunity Infants & young childrens are less able to resolve the infection  ~90% infected perinatally become chronic carriers

Hepatitis B virus/Epidemiology In US, new infected people/year and 4000 death Underdeveloped nations:  15% of the population infected during birth or chidhood

Hepatitis B virus/Epidemiology Asymptomatic carriers foster the spread of the virus Routes of spread: sexual, parenteral, and perinatal

Hepatitis B virus/Epidemiology Transmission:  Contaminated blood, blood components  Needle sharing  Acupuncture  Ear piercing  Tattooing  Very close personel contact The exchange of semen, saliva, vaginal secretions (e.g., sex, childbirth)

Hepatitis B virus/Clinical syndronnes Acute infection  Clinically apparent illness25%  Long incubation  Insidious onset  Prodromal period: fever, malaise, anorexia, nausea, vomiting,... jaundice, dark urine, pale stools  Icteric symptomes: jaundice, dark urine, pale stools

Hepatitis B virus/Clinical syndronnes Acute infection  Fulminant hepatitis in 1% of icteric patients  Hypersensitivity reactions Rash, Rash, polyarthritis, polyarthritis, Fever Fever Acute necrotizing vasculitis, Acute necrotizing vasculitis, Glomerulonephritis Glomerulonephritis

High-Risk Groups for Hepatitis B Virus Infection People from endemic regions (i.e., China, parts of Africa, Alaska, Pacific Islands) Babies of mothers with chronic hepatitis B virus Intravenous drug abusers People with multiple sex partners, homosexual and heterosexual Hemophiliacs and other patients requiring blood and blood product treatments Health care personnel who have contact with blood Residents and staff members of institutions for the mentally retarded Hemodialysis patients and blood and organ recipients

Hepatitis B virus/Clinical syndronnes Chronic infection  5-10% of people with HBV infections

Hepatitis B virus/Clinical syndronnes Primary hepatocellular carcinoma  80% of all cases of chronic HBV inf.  One of the three most common cause of cancer mortality in the world  May become the first vaccine- preventable human cancer  Latency period: 9 to 35 years

Primary hepatocellular carcinoma HBV may induce PHC by - promoting continued liver repair and -cell growth in response to inflammation and -tissue damage or by -integrating into the host chromosome and stimulating cell growth directly..

Primary hepatocellular carcinoma HBV may induce PHC by - Integration could stimulate genetic rearrangements or juxtapose viral promoters next to cellular growth- controlling genes. -Alternatively, a protein encoded by the HBV X gene may transactivate (turn on) the transcription of cellular proteins and stimulate cell growth..

Primary hepatocellular carcinoma The presence of the HBV genome may allow a subsequent mutation to promote carcinogenesis. The latency period between HBV infection and PHC may be as short as 9 years or as long as 35 years.

Interpretation of serologic markers of hepatitis B virus infection Hepatitis B virus/Laboratory diagnosis Interpretation of serologic markers of hepatitis B virus infection Serologic reactivity Disease state Healthy state EarlyEarly acute AcuteChronicLate acute Resolved vaccinat ed Anti-HBcAnti-HBeAnti-HBsHBeAgHBsAg Infectious virus / /

Hepatitis B virus/Prevention&Control Screening donated blood  HBsAg, anti-HBc Avoiding intimate personal contact with HBsAg (+)’s Avoiding the lifestyles that facilitate the spread of the virus (High risk groups) Vaccination

Hepatitis B virus/Prevention&Control Universal blood and body fluid precautions (refer to HIV and retroviruses lesson)

Prevention, and Control Transmission of HBV in blood or blood products has been greatly reduced by screening donated blood for the presence of HBsAg and anti-HBc. Additional efforts to prevent transmission of HBV consist of avoiding sex with a carrier of HBV and avoiding the lifestyles that facilitate spread of the virus. Household contacts and sexual partners of HBV carriers are at increased risk, as are patients undergoing hemodialysis, recipients of pooled plasma products, health care workers exposed to blood, and babies born of HBV-carrier mothers.

Prevention, and Control Vaccination is recommended for infants, children, and especially people in high-risk groups For newborns of HBsAg-positive mothers and people accidentally exposed either percutaneously or permucosally to blood or secretions from an HBsAg-positive person, vaccination is useful even after exposure. Immunization of mothers should decrease the incidence of transmission to babies and older children, also reducing the number of chronic HBV carriers. Prevention of chronic HBV will reduce the incidence of PHC

The HBV vaccines subunit vaccines. The initial HBV vaccine was derived from the 22-nm HBsAg particles in human plasma obtained from chronically infected people. The current vaccine was genetically engineered and is produced by the insertion of a plasmid containing the S gene for HBsAg into a yeast, Saccharomyces cerevisiae. The protein self-assembles into particles, which enhances its immunogenicity.

The HBV vaccines The vaccine must be given in a series of three injections, with the second and third given 1 and 6 months after the first. More than 95% of individuals receiving the full three-dose course will develop protective antibody. The single serotype and limited host range (humans) help ensure the success of an immunization program.

Universal blood and body fluid precautions are used to limit exposure to HBV. It is assumed that all patients are infected. Gloves are required for handling blood and body fluids; wearing protective clothing and eye protection may also be necessary. Special care should be taken with needles and sharp instruments. HBV-contaminated materials can be disinfected with 10% bleach solutions

Treatment, Prevention Hepatitis B immune globulin : within a week of exposure and to newborn infants of HBsAg-positive mothers to prevent and ameliorate disease. Chronic HBV infection:  lamivudine  adefovir dipivoxil  Famciclovir  Interferon-α

Hepatitis C and G viruses HCV HCV  was identified by molecular biologic means in 1989  Predominant cause of NANBH virus infections  Major cause of post-transfusion hepatitis (before routine screening of the blood supply for HCV)

Hepatitis C virus HCV  > (17x 10 7 ) carriers in the world but  Transmission similar to HBV but “Greater potential for establishing persistent, chronic hepatitis” CirrhosisHCC

Hepatitis C virus/Structure & Replication “HCV has never been isolated” “Only member of the Hepaciviridae” (family: Flaviviridae) Enveloped Positive-sense RNA  Encodes 10 proteins (2 glycoproteins, E1, E2)  6 groups of variants (clades), genotypes..

Hepatitis C virus/Pathogenesis Cell-mediated immunopathology is responsible mainly for producing the tissue damage Antibody to HCV is not protective! Immunity to HCV may not be lifelong

Hepatitis C virus/Epidemiology Is transmitted primarily in infected blood and sexually Almost all (>90%) HIV infected individuals who are/were IVDUs are infected with HCV Almost 20 % of Egyptian blood donors are (+)

Hepatitis C virus/Clinical syndromes 3 types of diseases Acute hepatitischronic persistant inf.Cirrhosis (15% recovery) (70%) (15%)

Hepatitis C virus/Clinical syndromes Acute HCV infectionsimilar to acute HAV/HBV, Inflammatory response is less intense Symptoms milder >80% asymptomatic

Hepatitis C virus/Laboratory diagnosis Anti-HCV with ELISA  Seroconversion within 7 to 31 weeks of infection HCV RNA with molecular techniques  RT-PCR Genotyping

Treatment interferon-α or pegylated interferon (treated with polyethylene glycol to enhance its biologic lifetime) with ribavirin

Hepatitis D virus ~ 15 million people are infected with HDV in the world Cause of 40% of fulminant hepatitis infections Unique  Uses HBV and target cell proteins to replicate and produce its one protein  “a viral parasite”  HBsAg is essential for packaging the virus

Hepatitis D virus/Structure&Replication ssRNA genome ~ 1700 nucleotides Rod shaped (circular) Virion size ~ HBV Delta Ag surrounded by HBsAg containing envelope

The delta hepatitis virion

Hepatitis D virus/Pathogenesis Similar to HBV :  Spread in blood, semen, and vaginal secretions  It can replicate and cause disease only in people with active HBV infections coinfected  A person can be coinfected with HBV & HDV, or superinfected  A HBV carrier can be superinfected with HDV Replication of HDV results in cytotoxicity and liver damage  Unlike HBV, damage to the liver occurs as a result of the directc cytopathic effect of the delta agent combined with the underlying immunopathology of the HBV disease

Hepatitis D virus/Epidemiology Worlwide distribution Endemic in southern Italy, the Amazon Basin, parts of Africa, and the Middle East Spread by the same routes as HBV

Hepatitis D virus/Clinical syndromes Increases the severity of HBV infections > fulminant hepatitis than other H. viruses

Hepatitis D virus/Laboratory diagnosis Ag, Ab, with ELISA or RIA HDV RNA

Hepatitis D virus/Tre-Pre-Co No known specific treatment Prevention of HBV HBV vaccine

Hepatitis E virus E-NANBH  Enteric/epidemic Non-A, Non-B hepatitis  Predominently spread by the fecal-oral route, esp. in contaminated water  Worlwide  Problematic in developping countries

Hepatitis E virus Epidemics in India, Pakistan, Nepal, Burma, North Africa, Mexico Symptoms and course similar to those of HAV Cause only acute disease Mortality rate associated with HEV disease is x10 times that associated with HAV disease (~1-2%)

Hepatitis E virus Mortality rate associated with HEV disease is x10 times that associated with HAV disease (~1-2%) Serious in pregnant women:  Mortality rate of approximately 20%

H EPATITIS G V IRUS HGV :known as GB virus-C [GBV-C] resembles HCV in many ways. a flavivirus transmitted in blood a predilection for chronic hepatitis infection It is identified by detection of the genome by RT-PCR or other RNA detection methods.