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Viruses of Humans. DNA VIRUSES. Parvoviridae Densivirinae Parvovirinae (Invertebrates) Bocavirus Parvovirus Dependoviruses (AAV) - Erythrovirus - Feline PV Helpers are * B19 parvovirus

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slide4
Parvoviridae

DensivirinaeParvovirinae

(Invertebrates)

BocavirusParvovirusDependoviruses(AAV)-Erythrovirus

- Feline PV Helpers are * B19 parvovirus

- Canine PV - adenoviruses * Semian PV

- Porcine PV - Herpesviruses

  • Mice PV - HPV

- Vaccinia virus

slide6
Parvoviruses are the simplest DNA viruses.
  • They are icosahedral in symmetry with a size of 18-26 nm.
  • The capsid consists of 60 capsomeres each of which is composed of two proteins; VP1 and VP2.
  • VP2 constitutes approximately 80% of the total protein mass of the virus.
slide7
VP1 and VP2 share significant sequence identity but VP1 is longer and has a unique region external to the capsid which is accessible to antibody binding.
  • VP1 is necessary for stable confirmation and induction of neutralizing antibodies.
  • The genome of B19 is 5.6 kb in length with a molecular weight of 1.5-1.8x106 Daltons.
slide8
Of all the DNA viruses, Parvoviruses seem to be among the most dependent on cellular function.
  • Dependoviruses (Adeno -associated viruses) commonly infect humans.
  • They do not appear to cause illness nor do they modify infection by their helper viruses.
  • AAV can become integrated at a specific site on the q-arm of chromosome 19 establishing latency with no known consequence.
slide9
Parvovirus B19 was the only human pathogen until September 2005 when a new member, Bocavirus, was described.
  • Parvovirus B19 was Discovered by Yvonne Cossart in 1975.
  • In 1981, It was linked to transient aplastic crisis(TAC), and in 1983 with fifth disease.
  • It has been classified in the genus Erythrovirus.
  • Bocavirus is a cause of respiratory tract infection
slide11
Human pathogens of the family belong to Papillomaviruses and Polyomaviruses only.
  • Virions are naked, icosahedral with a double stranded superhelical (circular) closed DNA genome.
  • They range in diameter form 40 to 45 nm for polyomaviruses and from 52 to 55 nm for papillomaviruses.
slide12
Their icosahedral capsid is composed of 72 pentamers.
  • Each capsomere is composed of 2 (L1, L2) peptides for papillomaviruses or 3 (VP1, 2, and 3) peptides for polyomaviruses.
  • Their genome is 5 - 8 Kbp
  • They are capable of causing lytic, chronic, latent, and transforming infections depending on the host cell.
papillomaviruses
Papillomaviruses
  • Induce warts (papillomas) in a variety of higher vertebrates, including man.
  • The viral nature of human warts was first indicated in 1907 by Ciuffo.
  • >100 different HPVs have been described on the basis of DNA sequence homology (> 50%) which fall into 16(A-P) groups that differ antigenically.
slide14
Genome: Two large (E1 and E2) and several smaller (E4-E7) ORFs and a late region with two large genes (L1 and L2).
  • The E region codes for proteins concerned with DNA replication, transcription and transformation.
  • The E1 and E2 proteins are both essential for replication.
  • The long control region (LCR) is concerned with the control of transcription.
transformation
Transformation
  • Binding of the E2 protein to an enhancer site on the LCR can upregulate transcription of E6 and E7.
  • Integration of the viral genome results in disruption of E1 and E2 with subsequent increase in expression of E6 and E7.
  • E7 binds Rb (P 105) and E6 binds to the tumor suppressor gene product P53 causing its rapid degradation.
polyomaviruses
Polyomaviruses
  • They were named so because of their capacity to cause different types of tumors.
  • Most of them display a narrow host range and do not productively infect other species.
  • Two viruses are definitely associated with human disease, JC virus )JCV (and BK virus(BKV).
slide17
The genome codes for large T and small t antigens.
  • They accumulate in the nucleus and stimulate cellular growth and are important for replication.
  • The early proteins are associated with immortalization and transformation.
  • Large T antigen binds to both Rb and P53 and prevents the induction of cell death.
introduction
Introduction
  • Rowe and colleagues (1953)
  • Hilleman and Werner (1954)
  • First given different names, these agents were called adenoviruses in 1956.
  • Today well over 100 members of the adenovirus group have been identified which infect a wide range of mammalian and avian hosts
introduction1
Introduction
  • Mastadenoviruses: infect mammals
  • Aviadenoviruses: infect birds.
  • 49 human adenovirus serotypes
  • Six groups (A-F)
structure
Structure
  • Naked icosahedral viruses with a diameter of 70-75 nm.
  • They have a characteristic Sputnik appearance.
  • Capsid is composed of 252 capsomeres

(240 hexons and 12 pentons). Of the hexons 60 are peripentons.

structure1
Structure
  • Each penton contains a base and a projecting fiber (10-30 nm).
  • The penton base and Fiber are cytotoxic and contain type-specific antigen.
  • The Fiber contains the VAP and acts as a hemagglutinin.
structure2
Structure
  • At least 11 polypeptides
  • The outer shell is composed of seven known polypeptides of which polypeptide II is the most abundant.
  • The hexon protein is comprised of three tightly associated molecules of polypeptide II.
structure3
Structure
  • Polypeptides VI, VIII, and IX are associated with the hexon protein as they likely stabilize the hexon capsomere lattice.
  • Five copies of polypetide III associate to form the penton base protein.
  • Polypeptide IV forms the trimeric fiber protein.
  • Peptide IIIa is penton associated
structure4
Structure
  • Polypeptide V bridges the core to the capsid
  • Polypeptide VII is a major core protein around which DNA is wrapped forming a histone -like center
  • Polypeptide Mu
  • A terminal protein which is attached to the 5-end of viral DNA (two copies per virion) and serves as a primer for DNAreplication.
structure5
Structure
  • DNA polymerase uses the terminal protein and a cytosine monophosphate as a primer.
  • Genome

- ds DNA of 34-45 Kbp with a molecular weight

of 20-25 x 106 Daltons.

- A terminal protein (55kd) covalently attached

to the 5-end (TP).

gene expression
Gene expression
  • Occurs in three phases termed pre-early, early, and late.
  • Most regulatory events in adenovirus gene expression occur at transcriptional or posttranscriptional steps.
  • Pre-early phase: Transcription of E1a. The E1a transcript is spliced to yield two E1a mRNAs. One of the proteins is a transcriptional activator that induces transcription of the early phase proteins.
gene expression1
Gene expression
  • Early phase: Transcription of (E1b, E2, E3, E4) and (L1) followed by splicing of RNA transcripts. Progression to the late phase of gene expression with the help of protein products of at least 6 early genes then takes place.
  • Late phase: Coincident with DNA replication and directed by the so-called major late promoter (20 distinct viral mRNAs). Transport of mRNAs to the cytoplasm. Splicing and transport involves

proteins producedin the early phase.

protein functions
Protein Functions
  • Adenoviruses employ both virally encoded and host proteins in replication.
  • E1A and virus-associated RNAs (VA RNAs) afford protection from α and ß interferons.
  • E1A and E1B activate host cell growth (S phase) and mediate transformation of cells in vitro
  • E1A inhibits apoptosis whereas E2 activates viral DNA replication and E3 antagonizesTNF and CTLs.
behavior in vitro
Behavior In Vitro
  • Replicate best in cells of human origin (HEK, A549, Hep-2 and Hela).
  • A group reactive epitope on the hexon is used to identify all adenovirus isolates.
  • Adeno CPE Consist of rounding and grape-like clustering of swollen infected cells.
  • Group and type- specific antigens exist in hexons and type specific antigen is present in pentons.
slide36
Membership in the family herpesviridae is based on the architecture of the virion.
  • Enveloped, icosahedral capsid (100-110nm)
  • Average size of the enveloped virus is 200 nm
  • Herpes viruses are highly disseminated in nature.
slide39
Eight human herpesviruses; HSV-1, HSV-2 VZV, HCMV, EBV, HHV-6, HHV-7 and HHV-8
  • Predominantly neurotropic(HSV-1, HSV-2, VZV) or predominantly lymphotropic

(EBV, HHV-6, HHV-7)

slide40
Virion size: 120-300 nm.
  • Variability is due to variable tegument thickness.
  • Genome: 80-150x106 (120-230 Kbp). Circularizes immediately upon release from capsid into nucleus.
biological properties
Biological Properties
  • They specify a large array of enzymes.
  • The synthesis of viral DNA and assembly of capsids occur in the nucleus.
  • The irreversible destruction of the infected cell.
  • They are able to remain latent in their natural hosts.
slide42
Herpesviruses also vary greatly in their biological properties.

- Host cell range.

- Efficiency and speed of replication.

- Site of latency.

- Clinical manifestations of diseases they cause.

classification
Classification
  • Three subfamilies, alpha, beta, and gamma on the basis of biological properties.
  • Classification into genera is based on:

- DNA sequence homology.

- Similarities in genome sequence rearrangement.

- Relatedness of viral proteins.

alphaherpesvirinae
Alphaherpesvirinae
  • HSV –1, HSV-2 and VZV.
  • Classified on the basis of :

- A variable host range

- Relative short reproductive cycle

- Rapid spread in culture

- Efficient destruction of infected cells

- Capacity to establish latency primarily but not

exclusively in sensory ganglia

betaherpesvirinae
Betaherpesvirinae
  • CMV, HHV-6, HHV-7.
  • Classified on the basis of :

- Restricted host range

- Long reproductive cycle

- Slow progress of infection in culture

- Enlargement of infected cells (cytomegalia)

- Latency in secretary glands, lymphoreticular

cells, kidneys and other tissues.

gammaherpesvirinae
Gammaherpesvirinae
  • EBV, HHV-8
  • Classified on the basis of :

- Limited host range.

- Replication In vitro in lymphoblastoid cells

- Cause lytic infections in some types of

epitheloid cells and fibroblasts

- Specificity for either T or B lymphocytes

- Latent virus is frequently demonstrated in

lymphoid tissue

herpes simplex viruses
Herpes Simplex Viruses
  • The first of the human herpesviruses to be discovered and the most intensively investigated of all viruses
  • Their attractions are their biologic properties
  • HSV-1 and HSV-2 have identical morphology and cross- reacting antigen
  • HSV infections of humans have been documented since ancient Greek times
viral dna
Viral DNA
  • It is composed of about 150 kbp with a molecular weight of100x106Daltons.
  • Two segments; short (S) and long (L), with reiterated sequences resulting in four isomeric forms.
  • It codes for more than 70 proteins.
gene expression2
Gene Expression
  • Three gene classes

- Alpha (immediate early)

- Beta (early)

- Gamma (late)

  • Alpha genes are responsible for the initiation of replication (5 genes).
  • Beta genes products include enzymes necessary for replication (e.g TK), and the replication proteins. They require functional alpha gene products for expression.
slide50
Initially, five HSV immediate-early genes are transcribed with the assistance of an activating protein carried in the tegument.
  • In turn, some of these five genes then activate expression of about another dozen early genes whose protein products are needed to replicate the viral DNA.
  • Following DNA synthesis, about another five dozen genes are activated. These genes encode structural components.
virion polypeptides
Virion Polypeptides
  • The virion contains more than 30 proteins designated as virion polypeptides (VP).
  • At least 11 are envelope glyocproteins
  • These are gB, gC, gD, gE, gG, gH, gI, gJ, gK, gL and gM.
  • gC, gE, gG, gI, gJ, and gM appear unnecessary for entry and egress in most infected cells.
slide52
gB, D and H are essential for the production of infectious virions
  • gB and gD are involved in adsorption and penetration into cells
  • gB and D share antigenic determinants between HSV-1 and HSV-2
  • gH is involved in the release of virus.
slide53
gG provides antigenic specificity to HSV (distinction between HSV-1 and HSV-2)
  • gC binds to C3b, whereas gE binds to Fc of IgG.
  • gI is thought to be involved with gE at the Fc receptor.
  • The role of gJ, gK, gL and gM are not well appreciated.
replication
Replication
  • Fusion of the envelope with the plasma membrane
  • Nucleocapsid is then transported to the nuclear pores where DNA is released into the nucleus.
  • Viral DNA synthesis by a rolling circle mechanism, yielding concatemers which are cleaved into monomers and packaged into capsids.
slide55
Viruses utilize more than one attachment pathway
  • HSV infects and replicates in two different cell types, epithelial cells and neurons.
  • It must be able to attach and infect at least three very different types of membranes.
  • It seems that multiple receptors exist
fate of the infected cell
Fate of the Infected Cell
  • Structural Alterations

- Chromatin changes

- Cell membrane alterations

- Polykaryocytosis

  • Host Macromolecular Metabolism
latency
Latency
  • In latently infected neurons, the viral genome acquires the characteristics of an endless or circular DNA.
  • The virus expresses no functions, which are required for the establishment or maintenance of the latent state.
  • In a fraction of neurons harboring latent HSV the virus is periodically reactivated
  • Latency of HSV does not appear to depend on the synthesis of virus-encoded proteins.
slide58

RNA transcripts in lieu of proteins, may be involved in HSV latency (latency associated-transcripts- LATs).

  • One possible mechanism is that LATs suppress and act as anti-sense to ICP0 (infected cell proteinα 0) which is expressed early during viral replication.
  • Current research suggests that the ability to hide may be achieved via modification to the cellular enzymes histone deacetylases (HDACs), namely HDAC1 and HDAC2.
  • Hypothetically, by interfering with the HDAC enzymes' effectiveness, it may be possible to block the virus's ability to hide from the immune system, leading to a complete elimination of the virus by the immune system.
slide60
Morphologically similar to HSV but antigenic relatedness is minimal.
  • One serotype with strains showing little variation.
  • Heberden distinguished varicella from smallpox in 1867
  • VZV has the smallest genome of all human herpes viruses (encodes 69 proteins).
major antigenic proteins
Major Antigenic Proteins
  • gE (Gp1), gB (GpII), gH (GpIII), gI (GP IV), and gC (GP V).
  • gE (GpI)

- Most abundant in VZV-infected cells.

- Binds to the FC of IgG

- Induces antibodies that have neutralizing activity in the presence of complement

  • gI (gpIV) is non covalently linked to gE in infected cells. Induces

neutralizing antibodies in the presence of complement

  • gB (GPII) elicits complement independent neutralizing antibodies. It appears to have a role in virus entry.
  • gH (Gp III) and gC (GpV) also induce antibodies with complement independent neutralizing function.
slide63
Discovered by Epstein, Barr and Achong in 1964 in lymphoma cells provided by Burkitt.
  • Two EBV types; 1 and 2
  • EBV differs in the predominance of a single surface glycoprotein (gp 350/220).
  • An additional minor protein (gp 85) also exists.
slide64
Characteristic features of EBV genome include:

- A size of 172 kbp

- A single over all format and gene rearrangement.

- Reiterated 0.5 Kbp terminal repeats.

- Reiterated 3 Kbp internal repeats, that divide the

genome into short and long unique sequences

(US, UL).

slide65
EBV has a very limited host range and tissue tropism defined by the limited cellular expression of its receptor.
  • This receptor is the CD21 molecule (CR2), the receptor for C3d. It is expressed on B cells and on epithelial cells of the oropharynx and nasopharynx.
  • EBV causes productive (lytic) infection of epithelial cells and latent infection in B lymphocytes.
  • EBNAs 1, 2, 3A, 3B and 3C, LPs, LMPs 1 and 2, EBER 1 and 2 are expressed in latently infected cells.
slide66
EBNAs and LPs are DNA binding proteins that are essential for establishing an infection (EBNA-1), immortalization (EBNA-2) and other purposes.
  • LMPs have oncogenic like activities
  • EBERs are most abundant in latently infected cells.
  • The viral gene products maintain the latent infection and cause the previously resting B lymphocyte to continuously proliferate.
  • Permissive cells allow the transcription and translation of the ZEBRA peptide, which activates the early genes of the virus and the lytic cycle.
slide69
Widely distributed in nature
  • Share common growth characteristics
  • Characteristic nuclear as well as cytoplasmic inclusions.
  • Distinguishing characteristics

- salivary gland tropism

- species-specificity

- slow replication in cultured cells.

slide70
The largest genome (240 kbp) that exists in four isomeric forms.
  • It is rich in direct and inverted repeats.
  • Purified CMV virions consist of at least 30 readily detected polypeptides
  • Two capsid, 8 envelope and as many as 20 tegument proteins.
envelope glycoproteins
Envelope Glycoproteins
  • Glycoprotein B (150 kd) is the major envelope glycoprotein of CMV that has the following functions:

- Virion penetration into cells

- Transmission from cell to cell

- Fusion of infected cells.

- a prominent target for neutralizing antibodies

slide73
Glycoprotein H (gP75) has the following functions:

- Target for complement-independent neutralizing

antibodies

- Cell-to-cell transmission of virus

- Membrane fusion.

- Essential for viral replication (entry).

slide74
Glycoprotein C II or gp47-52

- An abundant envelope glycoprotein

- Target for complement dependent

neutralizing antibody.

  • Glycoprotein 48; a minor envelope constituent.
  • Numerous strains with an overall genomic DNA sequence homology of approximately 95%.
slide75
CMV replication is slow and does not immediately kill cells or shut off host cell metabolic processes
  • Attachment proceeds rapidly and efficiently in both permissive and non permissive cells
  • The highly restricted host cell range of CMV is determined by a post penetration block involving restriction to viral gene expression (β2G)
slide77
The general properties of poxviridae include:-

-A large complex virion containing transcriptase and polymerase.

- A genome composed of a single linear ds DNA of 130-260 Kbp with a hairpin loop at each end (fused).

- A cytoplasmic site of replication.

slide78
The largest (240-300nm) and most complex of animal viruses.
  • Brick – shaped or ovoid.
  • Many of these viruses share antigenic determinants.
  • A biconcave core (dumbbell-like) covered by an outer membrane and an envelope.