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RNA VIRUSES Picornaviridae The smallest RNA-containing viruses known. Comprise one of the largest (230 members) and most important families of human and agricultural pathogens. The family is currently divided into five genera; Rhinoviruses, Enteroviruses, Aphthoviruses, Cardioviruses, and Hepatoviruses (REACH). Aphtovirus (foot-and-mouth disease virus):- Infects cloven-hoofed (footed) animals and occasionally humans. Cardiovirus:- Infects rodents Three genera; Rhinovirus, Enterovirus, and Hepatovirus include primary human pathogens with numerous serotypes. Genus Rhinoviruses Enteroviruses Virus Serotypes > 100 Polio viruses Coxsackie viruses A 3 B Echoviruses Hepatovirus Total 23 6 28 1-22, 24 (23= echorviruses 9) 1-6 1-7,9,11-21, 24-27,29-33 Echo 8 = Echo 1 Echo 10 = Reovirus 1 Echo 28= Rhino 1A Echo 34 = Coxsackie A 24 Echo 22,23= Parechovirus *Parechoviruses 2 *Enteroviruses 68-71 4 Previously Echo 22 and 23 New naming system since 1967 Hepatitis A virus Previously enteroviruses 72 1 67 Enteroviruses and Hepatovirus differ from Rhinoviruses in: - Stability at pH 3 - Optimum T º of growth - Mode of transmission - Diseases caused Enterovirus Particles The virion is roughly spherical, naked, and range in diameter from 24 to 30 nm. 60 subunits make up the icosahedral capsid each of which is composed of four polypeptide chains, VP1VP4 VP1, 2 and 3 are exposed at the virion surface, whereas VP4 lies buried in close association with the RNA core. Of the four proteins, VP1 exhibits the greatest sequence variability and VP4 the least. VP1 is also the dominant protein, playing key roles in surface topography, antigenicity, receptor binding, and probably viral uncoating. Genome is a ss RNA ( 7500 nt) of positive polarity, polyadenylated at 3- and has a protein of 22 to 24 amino acids (VPg) at the 5- end. Receptors The receptors for polioviruses, Coxsackie viruses, echoviruses, and the major serogroup of rhinoviruses have all been mapped to human chromosome 19. The receptors for polioviruses and human rhinoviruses have been identified as members of the Ig superfamily, whereas the receptor for echoviruses has been identified as a member of the integrin family. Virus - Rhinovirus (major) - Rhinovirus (minor) - Polioviruses - Coxsackie A - Coxsackie B - Echovirus Receptor ICAM-1 LDL-R PVR (similar to ICAM-1) CD155 ICAM-1 Unknown DAF, VLA-2 Enteroviruses Arildone (pleconaril) contains a 3-methyl- isoxazole group that binds to the floor of the VP1 canyon and alters its conformation to prevent the uncoating of the virus. Poliovirus produces a protease that degrades the 200.000 Dalton cap-binding protein of eukaryotic ribosomes, thereby blocking the translation of cellular mRNA. Orthomyxoviridae INFLUENZA VIRUS ORTHOMYXOVIRUSES HA - hemagglutinin NA - neuraminidase helical nucleocapsid (RNA plus NP protein) lipid bilayer membrane polymerase complex M1 protein type A, B, C : NP, M1 protein sub-types: HA or NA protein Among the RNA viruses, influenza is very special in that all of its RNA synthesis take place in the nucleus. Short capped primers are generated from host cell RNAs by an influenza virus-encoded cap-dependent endonuclease. Influenza virus mRNAs undergo splicing in the nucleus. Classification The family contains two genera: Influenza A and B viruses, and influenza C virus. Genera are distinguished on the basis of antigenicity of nucleoprotein (NP) and matrix (M) proteins. Influenza A viruses are divided into subtypes based on the antigenicity of HA and NA glycoproteins. Distinguishing Characteristics Influenza A viruses naturally infect humans, several other mammalian species and a wide variety of avian species whereas Influenza B and C are human pathogens. The surface glycoproteins of influenza A virus exhibit much greater amino acid sequence variability than their counterparts in influenza B virus. Influenza C has a single multifunctional glycoprotein. Influenza A and B viruses contain 8 RNA segments, whereas influenza C contains 7 segments Virion Structure Influenza A and B are morphologically indistinguishable but there are morphological features that distinguish influenza A and B viruses from influenza C virus. The RNPs consist of four protein species and the RNA genome which occurs in eight separate segments containing 10 genes. The segments are complexed with nucleoprotein to from a nucleocapsid with helical symmetry. Genomic segments range from 890 to 2340 bases. Replication Unlike replication of other RNA viruses, replication of orthomyxovirus depends on the presence of active host cell DNA synthesis. Replication in the nucleus is necessary because the virus lacks capping and methylating enzymes activities. The virus scavenges cap sequences from the nascent mRNA generated in the nucleus and attaches it to its own mRNA. Genome Organization RNA segment 1 codes for PB2 RNA segment 2 for codes PB1 RNA segment 3 for codes PA RNA segment 4 for codes HA RNA segment 5 for codes NP RNA segment 6 for codes NA RNA segment 7 for codes M1 and M2 RNA segment 8 for codes NS1, and NS2 Virion Proteins PB2, PB1 (Basic), PA (acidic) NP HA (16 subtypes) HEF (Influenza C) NA (9 subtypes) M1 and M2 NS1 and NS2 Genetics RNA segment Reassortment (Antigenic shifts) RNA Mutations (antigenic drifts) RNA Recombination Nomenclature - A/Swine / lowa/15/30/H1N1 - A/ Bangkok/1/79/H3N2 Paramyxoviridae Enveloped viruses with a negative single stranded nonsegmented RNA genome. They have special relationships with orthomyxoviruses and rhabdoviruses. They encode and package their own RNA transcriptase. They range in size from 150 – 350 nm Classification The Paramyxovirinae Paramyxovirus: Parainfluenza virus types 1 and 3. Rubulavirus: mumps virus, parainfluenza virus types 2, 4a and 4b. Morbillivirus: measles virus. The pneumovirinae Pneumovirus: Respiratory Syncytial Virus (RSV) Nucleoprotein (NP) Phosphoprotein (P Protein) large (L) protein The matrix (M) protein Envelope Glycoproteins - Attachment protein (HN,H, G) - Fusion Protein (F) Other proteins - SH, C, V, W, I, D, NS1 and NS2. Parainfluenza Virus ssRNA virus enveloped, pleomorphic morphology 5 serotypes: 1, 2, 3, 4a and 4b No common group antigen Closely related to Mumps virus Parainfluenza Viruses Important respiratory tract pathogens of infants and children causing 30-40% of such infections. They are second only to RSV as a cause of serious respiratory tract disease in infants and children (HPIV 1-3). Pleomorphic, 150-200 nm in diameter, enveloped with HN and F envelope glycproteins. Respiratory Syncytial Virus (RSV) RSV is the most important cause of viral lower respiratory tract disease in infants and children worlwide. RSV infection is an important agent of disease in immunosuppressed adults and the elderly. Ranges in diameter from 150-300 nm Research on RSV has been impeded because - It grows poorly in tissue culture and most exprerimental animals - it does not shut off host macromolecular synthesis - The virion is unstable. RSV survives on surfaces for up to 6 hours and on gloves for less than 2 hours. The virus loses viability with freeze-thaw cycles, in acidic conditions and with treatment by disinfectants. It encodes a larger number of mRNAs than do the paramyxoviruses (10 compared with 6 or 7) Additional genes are; SH, M2, NS1, and NS2 Although six proteins appear to correspond (N, P, M, G/H/HN; F and L) only F and L exhibit unambiguous sequence relatedness between the two subfamilies. Variation in the G glycoprotein (RSV-A and B) RSV utilizes ICAM-1 as its receptor. Mumps Virus “to mump” means to grimace or grin. The virion is 120 – 200 nm in diameter Contains in addition to the six major proteins; V (viral) protein and S (soluble) protein. One serotype. MEASLES (RUBEOLA) Measles is a relatively new disease of humans. Probably it has evolved from an animal morbillivirus (rinderpest). It is related to canine distemper virus. Abu- Becr Al- Razi of 10th century is credited with distinguishing smallpox from measles. He referred to measles as “hasbah eruption” in Arabic and regarded it as a modification of smallpox. It is highly infectious and almost always produces clinical disease in those infected. Virion is similar to other members of the paramyxoviridae but it lacks the neuraminidase. Membrane cofactor protein (MCP) or CD46 is the receptor for the virus. Measles virus is a stable monotypic virus with some degree of variability (strains). Human Metapneumovirus In 2001, van den Hoogen and colleagues reported that they had isolated a paramyxovirus from 28 young children in the Netherlands identified as a new member of the metapneumovirus genus by: - Virological data - Sequence homology - Gene constellation Previously, avian pneumovirus was the sole member of this recently assigned genus, hence the provisional name for the newly discovered virus: human metapneumovirus. hMPV Features Negative stranded RNA virus Paramyxoviridae family Related to avian pneumovirus and turkey rhinotracheitis virus Causative agent of respiratory tract disease in humans Most children are seropositive by the age of 5 years 2 genetic clusters of hMPV that may represent different serotypes Rubella virus Rubella virus is a member of the togaviridae but unlike most other togaviruses, rubella virus has no known invertebrate host, and the only known natural reservoir for rubella virus is man. Rubella virus is a spherical, icosahedral, enveloped particle that measures 60-70 nm in diameter. It has a +ss RNA genome of about 10.000 nt that is encased by multiple copies of the capsid protein (C). Two glycoproteins, E1 and E2, are embedded in the envelope Rhabdoviridae A large number of member viruses that are serologically unrelated. Rabies belongs to the genus lyssa virus (rabies in Greek means mad or frenzy). It is bullet shaped, enveloped and has a diameter of 75X180 nm. Rabies Virus G, M, L, N, and NS Proteins The genome is helical and is associated with N protein. Virions bud from the endoplasmic reticulum Replication of rhabdoviruses is followed by cell death except for rabies virus which is nonlytic causing no discernable damage CORONAVIRUSES HISTORY AND CLASSIFICATION • Avian Infectious Bronchitis (IBV) (Schalk and Hawn, 1931). • Recovery of virus in the Laboratory (Beaudette and Hudson 1937). • • Discovery of human coronaviruses (Tyrrell and Bynoe, 1965). Distinctive morphology. Genome Structure Human Coronaviruses Genus Coronavirus Species HCoV-229E HCoV-OC43 SARS- CoV HCoV-NL63 HCoV-HKU1 HCoV-EMC • Responsible for about 10-20% of common colds re-infection is common infections year-round, most prevalent in fall and spring incubation period about 2 to 5 days VIRION STRUCTURE There is considerable diversity in both the lengths and nucleotide sequences of the S1 glycoproteins of different coronaviruses and even of different strains of a single coronavirus. This diversity in S1 probably results from mutation and recombination between coronaviruses and strong positive selection in vivo. Functions of Coronavirus Proteins Membrane (M) glycoprotein May determine budding site on intracellular membranes Essential for envelope formation May interact with viral nucleocapsid May induce alpha interferon Functions of Coronavirus Proteins Spike (S) glycoprotein Binds to specific host cell receptor glycoprotein May induce fusion of viral envelope with cell membrane Induces cell fusion Binds immunoglobulin at Fc receptor site Binds to 9-O-acetylated neuraminic acid Induces neutralizing antibody Elicits cell-mediated immunity Coronavirus Stability Stable In body fluids (e.g. urine and faeces) for up to 4 days. For 21 days at cold temperature (4 and -80ºC). At a pH of 6. Inactivated rapidly: At a mild alkaline pH. By disinfectants By heating to 56 ºC REPLICATION OF CORONAVIRUSES Primary translation. Transcription of viral RNA. Replication of viral RNA. Processing and intracellular transport of viral proteins (S glycoprotein). Assembly and release of virions. Coronavirus Genetics Variation is due to Mutation and Recombination Mutation High frequency (several point mutations during each round of replication). Analysis has shown extensive sequence variability in S and N genes especially due to deletion mutations. The most striking example of the biological importance of deletion mutations is the emergence of porcine respiratory coronavirus (PRCV) from transmissible gastroenteritis virus (TGEV) which causes epizootic enteric infection of pigs. In the early 1980s, PRCV emerged in Europe as a new virus that causes widespread, devastating epizootics of respiratory disease in pigs. Recombination • High frequency (up to 25%). Mechanism is by discontinuous transcription and polymerase jumping (Copy-choice). Example is acquisition of HE glycoprotein from influenza C The capacity of coronaviruses both to recombine and to mutate suggests that diversity will also be a feature of human coronaviruses and that changes in pathogenicity may occur over time (Kenneth McIntosh, 1996). Propagation and Assay in Cell Culture In tissue culture, coronaviruses have a latent period of about 5 to 7 hours. Infectivity of virions is fairly stable at pH 6.0, but rapidly inactivated at mildly alkaline pH. Coronaviruses can cause either cytocidal or persistent infections of cells in vitro and in vivo, depending on the virus strain and the host cell. None of the human coronaviruses, except HCoV-EMC, grows well in cell culture without extensive adaptation by passage. They have been propagated in human embryonic tracheal organ culture, in primary or secondary human embryonic kidney cell lines, in many diploid human fibroblast cell lines, and in few heteroploid lines. The most sensitive cell line for isolation of virus from clinical specimens appears to be the diploid intestinal cell line MA – 177. The highest titers of both 229E and OC43 are obtained by growth in human rhabdomyosarcoma cells. Reoviridae Respiratory Enteric Orphan viruses (Albert Sabin, 1959) Non enveloped with double-layered protein capsid, containing 10-12 segments of the double-stranded RNA genomes (double : double). Stable over wide PH and temperature ranges and in air-borne aerosols. Human Pathogens - Orthoreoviruses - Rotaviruses - Orbiviruses - Coltiviruses Rotaviruses cause human infantile gastroenteritis. They account for approximately 50% of all cases of diarrhea in children requiring hospitalization because of dehydration. In underdeveloped countries, rotaviruses may be responsible for causing as many as 1 million deaths each year from uncontrolled viral diarrhea. Rotavirus Particle Proteolytic cleavage of the outer capsid activates the virus and produces an intermediate/infectious subviral particle (ISVP). Rotaviruses resemble enveloped viruses and they acquire an envelope and loose it during replication. Reassortment of gene segments can occur and thus create hybrid viruses. Gene segment Protein location VP1 VP2 VP3 (inner capsid) (inner capsid) (inner capsid) VP4 (outer capsid spike at vertice) NS53 VP6 Function Polymerase Transcriptase mRNA capping Activation by protease to VP5 and VP8 in ISVP, HA and VAP RNA binding (inner capsid) Groups (A-E) and Subgroups (I,II) Major structural protein binds to NS28 at ER and promote outer capsid assembly NS34 NS35 VP7 NS28 NS26 (Outer capsid) Serotypes ( 1-7) Type-specific antigen major, outer capsid component Promote inner capsid binding to ER, transient envelopment of outer capsid Rotaviruses are found in many different mammals and birds. Rotavirus is stable at room temperature and to treatment with detergents, pH extremes of 3.5 to 10 or even repeated freezing and thawing. Infectivity is enhanced by proteolytic enzymes such as trypsin. Human and animal rotaviruses are divided into 7 serotypes on the basis of antigenicity of VP7 and VP4 5 groups on the basis of electrophoretic mobility of VP6 DNA 2 subgroups on the basis of antigenicity of the inner capsid protein VP6. Caliciviruses and Related Agents Caliciviruses are 27-38 nm, non enveloped, icosahedral viruses with a (+) ss RNA genome (7500 bases). Norovirus (previously called Norwalk agent) was discovered by EM in stool from adults during and epidemic of an acute gastroenteritis in 1968 in Norwalk, Ohio. Noroviruses Noroviruses (genus Norovirus, family Caliciviridae) are a group of related, single-stranded RNA, nonenveloped viruses that cause acute gastroenteritis in humans. Norovirus was recently approved as the official genus name for the group of viruses provisionally described as “Norwalklike viruses” (NLV). Currently, there are at least five norovirus genogroups (GI, GII, GIII, GIV and GV), which in turn are divided into at least 31 genetic clusters. Astroviruses have a five or six-pointed star shape of 28-30 nm in diameter with an icosahedral symmetry. The Retroviridae Genome - 2 identical molecules of ss RNA - Gene order is invariably; gag- pro/ pol - env. - other genes are present in some viruses. Mode of Replication Classification - 6 genera, and human pathogens belong to 2 genera; HTLV-BLV and Lentiviruses. HTLV-1 (1981), HTLV-2 (1982) Human Immunodeficiency Viruses (HIV) Pneumocystis carinii and Kaposi’s sarcoma among initial “ 4 H ” club of AIDS. Isolation of LAV by Montagnier In April 1983. A year later, Galo at NIH, isolated HTLV-3. HTLV-3 and LAV showed 98-99% identity. LAV-2 and HTLV-4 were isolated In 1986 In 1986, the ICVT renamed the viruses HIV-1 and HIV-2. HIV-1 and HIV-2 are lentiviruses (lenti =slow). HIV-1 and HIV-2 share about 40% of their genome sequence. Similarity is remarkable between HIV-1 and SIVcmp, and between HIV-2 and SIVsmm. Greatest sequence variation exists in the env. gene The genome is composed of 2 identical copies of 9.749 kb ss RNA of positive polarity. A tRNA molecule is positioned near the 5- end of each strand, with 10-50 copies of reverse transcriptase. The tRNA is used as a primer for DNA synthesis. At each end, there are LTR sequences which contain promoters, enhancers, and other gene sequences for binding different cellular transcriptional factors. Although of positive polarity, HIV genome is not infectious cleavage P55 → P17(MA), P24(CA), P9(NC), and P7 (?). P100 → P10 (pro) P51/P66 (RT/ RNAse H), P32(1N). P160 → gP120 (SU) and gP 41(TM). HIV Genome Other Genes of HIV tat: rev: vif: vpr: vpu: nef: Positive regulator of transcription Regulator of viral expression Affects viral infectivity Positive regulator of transcription, augments virion production. Down regulates CD4 So-called negative-regulation factor. It augments viral replication and down regulates CD4 Antigenic Variation The reverse transcriptase is very error prone and lacks proof reading which contribute to HIV diversity. The immune response of the host is unable to completely curtail viral replication. Virus gene products may be relatively invisible to the immune response and the virus may be able to mask or change its antigenic specificity. The envelope gene displays frequent mutations. HIV envelope glycoproteins have two unusual features. - They are extensively glycosylated - They contain hypervariable regions that permit the virus to present new antigenic configurations to the host. HIV can constantly vary its surface antigenic composition which may allow it to avoid inactivation. Such a mechanism hinders the development of an effective vaccine containing the surface glycoproteins. Major sequence differences exist between the two HIV types; antibodies against the surface glycoprotein of HIV-1 only partially cross react with HV-2. Arboviruses Epidemiologic classification, but taxonomically diverse. More than 400, all of which are RNA viruses and about 100 of them infect humans. They establish life-long infections of arthropods and humans are accidentally infected. They have strong dependence on climatic conditions. Families Togaviridae: VEE, EEE, WEE Falviviridae: Dengue, YF, West Nile fever, JE, St. Louis Encephalitis, Kyasanur Forest Disease, Omsk H.F. Bunyaviridae: CE, Rift valley fever, Crimean- Congo virus, Sand fly fever, Hantaan virus Arenaviridae: Junin, Machupo, Sabia, Guanarito, Filoviridae: Lassa Marburg and Ebola viruses The Bunyviridae A supergroup of at least 300 viruses. Spherical, enveloped, 90-120 nm, with 3 segments of ambisense ssRNA. Four genera; Bunyavirus, Phlebovirus, Niarovirus and Hantavirus. All, except Hantaviruses, are arthropod borne. Hantaviruses are rodent borne. Arenaviruses Pleomorphic, enveloped viruses of 120 nm in diameter 2 circles of ambisense ss RNA A sandy appearance (arenosa = sandy in Greek) because of the ribosomes in the virion. Filoviruses Filamentous, enveloped, with 80nm in diameter. - ss RNA of helical symmetry They vary in length from 800 to 14.000nm. Hepatitis Viruses A large number of viruses can cause hepatitis (EBV, CMV, VZV, HSV, YF, Lassa virus … etc). There are other viruses, however, that only cause hepatitis. At least six viruses, A through E and a newly discovered virus GB, are considered hepatitis viruses. Hepatitis viruses differ greatly in their taxonomy, structure, mode of replication and mode of transmission as well as in the course of the disease they cause. Hepatitis A Virus It is the cause of infectious hepatitis, a term that was coined in 1912 to describe the epidemic form of the disease. The virus was first isolated in 1973 by Feinstone et al using IEM. Previously classified as enterovirus 72, HAV has been put in a separate genus; hepatovirus Differences Between HAV and Enteroviruses HAV nucleotide and amino acid sequences are dissimilar to enteroviruses. HAV is difficult to grow in cell culture and it usually replicates very slowly causing no CPE (nonlytic). HAV is stable at a PH of 1 HAV has only one serotype and one neutralization site is dominant. Enterovirus -specific monoclonal antibody does not react with HAV. Virus Structure HAV is a naked 27-32 nm icosahedral virus with a ssRNA genome of positive polarity. Its genome is 7.5 kb in length, polyadenylated at the 3- end and carries a protein (VPg) at the 5- end. Hepatitis A Virus Hepatitis B Virus Hepatitis B Virus Hepatitis B virus is unusual among animal viruses in that: o Infected cells produce multiple types of virus-related particles. - 42 nm double-shelled particles (Dane particles) - 20 nm spheres, usually present in 104-106 fold excess over Dane particles. - Smaller quantities of filaments of 20 nm diameter and variable length. Hepatitis B Virus o o o The genome is partially double stranded. It replicates utilizing an RNA intermediate and has a reverse transcriptase. It is unusually stable for an enveloped virus. The Dane particle is the only infectious form. Envelope : HBsAg. Core : HBcAg. With less than 3200 nucleotides, HBV has the smallest genome of any human virus. HBV genome is relaxed circular partially duplex DNA species, whose circularity is maintained by 5- cohesive ends. The genome has a coding organization that is highly compact and over half of the sequence is translated in more than one frame. HBV uses its genome economically by encoding different proteins within the same region of DNA in different reading frames. About half of the genome’s nucleotides are used to code simultaneously for different proteins, and all code for at least one protein. The regulatory signals overlap with coding sequences and are not separate regions. Four ORFs are present in the DNA. - ORF P: encodes the viral polymerase and the terminal protein found on minus strand DNA. - ORF C: encodes the core protein (C antigen) - ORF S/pre-S: encodes the HBsAg. - ORF X: encodes a protein that enhances the expression of heterologous and homologous genes. The reading frame for HBsAg was shown to have two in-frame initiation codons which result in three products L, M, and S. The bulk of HBsAg is the S protein, M protein accounts for 5-15% of it and L for 1-2%. The S (gp 27, 24-27 kD) glycoprotein is completely contained in the M (gp36; 33-36 kD) glycoprotein which is contained in the L (gp42; 39-42 kD) glycoprotein. The coding organization of the core protein is similar, two in-frame AUGs were found in the core ORF. Initiation at the upstream AUG gives rise to a Crelated protein that is secreted from infected cells into circulation (HBeAg). Three major mRNAs are produced 1) 2100 b mRNA: HBsAg (S, M) 2) 2400 b mRNA: HBsAg (L) 3) 3500b mRNA: HBcAg, HBeAg, polymerase and a protein primer for DNA replication and it acts as a template for genome replication In addition to a minor mRNA (700 b) which codes for X protein (a transactivator of transcription and a protein kinase). HBsAg contains the group specific antigenic determinant termed a and type specific determinants termed d or y and w or r Type specific determinants behave like mutual alleles. Combinations result in four possible antigenic subtypes (adw, adr, ayw, ayr). HBV Variation Eight genetic groups (A-H Genotypes) and a possible 9th type (I?) and Within genotypes 24 subtypes have been described which differ by 4-8% of the genome. HBV Antibody Escape Mutants Substitution of arginine for glycine at aa 145. Immunity to vaccine does not neutralize mutant. Failure to detect HBsAg in donated blood HBV Precore Mutants Detected in patients with severe chronic liver disease and who may have failed to respond to interferon therapy (increased pathogenicity) Polymerase Variants ( drug resistance) Replication Virus particles acquire an envelope in the endoplasmic reticulum or proximal Golgi The surface antigen is glycosylated in the Golgi apparatus. Virions are then secreted via the constitutive pathway of vesicular transport. Hepatitis D virus (Delta virus) HDV is not a true virus but a defective virus or a natural satellite of HBV Delta antigen is present in two forms, small (short) with 24 kd and large (long) with 27kd. The short form which is more abundant is required for RNA replication whereas the long form suppresses viral RNA replication and is required for packaging of the HDV genome by HBsAg. HDV replicates only in HBV-infected cells and direct pathologic changes are limited to the liver, the only organ in which HDV has been shown to replicate. HDV itself seems to be cytopathic and HDV antigen (delta) may be directly cytotoxic. Hepatitis C virus Was discovered in 1989 (post transfusion hepatitis). Flaviviridae, genus Hepacivirus (HCV and GBV-C). Enveloped, 55-65 nm. Six genotypes with several subtypes for each genotype + ss RNA genome - 9.4 kb - over 98% contains protein coding sequence. - a single large ORF Hepatitis C Virus capsid Envelope protein c22 protease/ helicase c 33 RNA dependent RNA polymerase c-100 5’ 3 ’ core E1 E2 hypervariable region NS2 NS3 NS4 NS5 The genome codes for nine proteins; 3 structural and 6 nonstructural. The structural proteins are; core protein (P22), E1(gp76), and E2 (gp35) which are envelope glycoproteins. The nonstructural proteins are; NS2, NS3, NS4A, NS4B, NS5A, and NS5B. HCV has circumvented the cap requirement by evolving an Internal Ribosome Entry Site (IRES) at its 5- end. Hepatitis E Virus Recognized as a distinct disease in 1980. Virion is 32-34 nm in diameter, nonenveloped, with an icosahedral symmetry. Although it was originally classified in the Caliciviridae family, the virus has since been classified into the genus Hepevirus, but was not assigned to a viral family. The genome is approximately 7200 bases in length, is a polyadenylated single-strand RNA molecule that contains three discontinuous and partially overlapping ORFs ORF1 encode methyltransferase, protease, helicase, and replicase ORF2 encode the capsid protein ORF3 encodes a protein of undefined function. An in vitro culture system is not yet available.