dna virus

HUMAN DNA VIRUSES

Ronald Luftig Ph.D.Louisiana State UniversityProfessor and HeadDepartment of Microbiology,Immunology & Parasitology

www.freelivedoctor.com

OBJECTIVESOBJECTIVES

General replication cycle of DNA viruses using Adenovirus as a model

Unique replication features of all DNA viruses, including Herpes,Papovaviruses and Hepadnaviruses

Disease features of different Adenovirus types, Poxviruses andParvoviruses

vCJD and Mad Cow disease


PARVOVIRUSPARVOVIRUS SS linearSS linear --

PAPOVAVIRUSPAPOVAVIRUS DS, circular DS, circular - -

ADENOVIRUSADENOVIRUS DS, linearDS, linear --

HERPESVIRUSHERPESVIRUS DS, linearDS, linear ++

POXVIRUSPOXVIRUS DS, linearDS, linear ++

HEPADNAVIRUSHEPADNAVIRUS DS, circular DS, circular + +

DNA VIRUS GENOME EnvDNA VIRUS GENOME Env


PARVOPARVOVIRUSVIRUS = Small= Small

B19 - infects erythroid progenitor cellsB19 - infects erythroid progenitor cellsAdeno-Associated Virus AAV Adeno-Associated Virus AAV (helper-dependent parvoviruses)(helper-dependent parvoviruses)

PAPOVAVIRUSPAPOVAVIRUSPapilloma &Papilloma &

Polyoma VirusesPolyoma Viruses

numerous types of numerous types of Human Papilloma Virus (HPV)Human Papilloma Virus (HPV) – Warts – Warts

BK and JC Virus (BKV, JCV)BK and JC Virus (BKV, JCV)BK - kidney; JC - brain - problems in the BK - kidney; JC - brain - problems in the immunocompromised;immunocompromised;SV40 (monkey)-SV40 (monkey)- vacuolating virus vacuolating virus

ADENOVIRUSADENOVIRUS49 serotypes in humans49 serotypes in humansrespiratory disease, epidemic respiratory disease, epidemic conjunctivitis, gastroenteritisconjunctivitis, gastroenteritis

HERPESVIRUSHERPESVIRUS8 types8 types in humansin humans

herpes B virus - macaquesherpes B virus - macaques

Herpes Simplex 1&2, Varicella-zoster, Herpes Simplex 1&2, Varicella-zoster, Epstein-Barr, Cytomegalovirus, Human Epstein-Barr, Cytomegalovirus, Human Herpes 6, 7,8; HHV6, HHV7= Roseolovirus Herpes 6, 7,8; HHV6, HHV7= Roseolovirus HHV8 = Kaposi’s sarcoma associatedHHV8 = Kaposi’s sarcoma associated

POXVIRUSPOXVIRUS Variola (small pox), Vaccinia (small pox Variola (small pox), Vaccinia (small pox vaccine), Molluscum contagiosumvaccine), Molluscum contagiosum

HEPADNAVIRUSHEPADNAVIRUS Hepatitis B virus (HBV) Hepatitis B virus (HBV) www.freelivedoctor.com

ADENOVIRUSESADENOVIRUSES


Adenoviruses encompass 49 serotypes or six subgroups (A-F).

In humans, they infect cells in tissues at the portal of entry. Many serotypes commonly infect local lymphoid tissue (adenoids, tonsils, Peyer’s patches) in persistent or latent fashion, perhaps for life.

Adenoviruses also replicate in the intestine, where they may persist for months and are usually not pathogenic. NO viremia or disseminated diseases occurs except in immuncompromised patients.

GENERAL ADENO PROPERTIES


As a general rule all DNA viruses replicate in the nucleus, except the Pox viruses which replicate in the cytoplasm

We will use Adenoviruses as a model system for understanding replication of DNA viruses in general

Most DNA viruses are naked (see model of soccer ball), with 12 blue penton bases on the vertices and 20 yellow hexons on the rest of the face. Both pentons and hexons are known as capsomers and form the capsid which encloses the nucleic acid as discussed by Dr. Amedee

For Adenovirus, there are 252 capsomers 12 on the vertices and 240 on the faces. In the soccer ball model there are 32 capsomers to give you an idea of size

ADENOVIRUS REPLICATIONADENOVIRUS REPLICATION


1.Protomers

2.Capsomers

3.Pro-Capsid

4.MatureCapsid


Adenovirus - Adenovirus - Icosahedral CapsidsIcosahedral Capsids


Adenovirus 2 Genome Adenovirus 2 Genome MapMap


In adenovirus, the first step involves attachment of the fiber to a host cell receptor.

This is called the CAR (coxsackie-adenovirus receptor).

Then after entry the particle moves into an endosomal vesicle to the nucleus where the DNA is uncoated into the nucleus through the nuclear pore.

This sets up the general replication scheme: first of enzymes to help the virus replicate (early stage), then double-stranded DNA replication (semi-conservative mode) begins (late stage), followed by translation of structural proteins, such as the penton and hexon precursors.

STAGES OF ADENO REPLICATION ISTAGES OF ADENO REPLICATION I


Adenovirus ReplicationAdenovirus Replication

Endosome

Virion

IntegrinsCAR

Virion DNA

Nuclearpore

Nucleus

Cytoplasm



Endosome

Early mRNAs

Earlyproteins

Virion

IntegrinsCAR

Virion DNA

Modulate Cell Cycle

Shut down host mRNA transport

Block CTL Response

Nuclearpore

Nucleus

Cytoplasm


STAGES OF ADENO REPLICATION IISTAGES OF ADENO REPLICATION II

After translation the proteins accumulate in the nucleus and together with newly made (nascent) viral DNA assembly into virions.

After 2-3 days of accumulation the cells lyse and release several hundred adenovirus particles in a burst.



Endosome

Late mRNAs

Early mRNAs

EarlyproteinsLate

proteins

Virion

IntegrinsCAR

Virion DNAModulate Cell Cycle

Shut down host mRNA transport

Progeny DNA

Cell Lysis

Block CTL Response

ProgenyVirus

Nuclearpore

Nucleus

Cytoplasm


ADENOVIRUS AND HUMAN DISEASEADENOVIRUS AND HUMAN DISEASE

DISEASE ADENOVIRUS

Mild pediatric respiratory disease type 1, 2 & 5 (prevalent 0-6 yrs.)

Acute respiratory disease (ARD) (5-8% adults types 3, 4, 7, 14, 11 & 21& up to 50-80% of military recruits)

Pharyngoconjunctival fever, eye types 3, 4, 7, 14, & 21involvement as long as 3 weeks

Epidemic keratoconjunctivitis “shipyard eye”, highly type 8 – and type 19contagious, severe, but usually no sequelae

Infantile diarrhea – prevalent in third world and migrant types 40 & 41 workers


Resist drying, detergents, mild Resist drying, detergents, mild chlorine, and GI tract secretionschlorine, and GI tract secretions

Spread exclusively human-to-Spread exclusively human-to-humanhuman

May be shed intermittently and May be shed intermittently and over long periods from pharynx over long periods from pharynx and fecesand feces


Contagious

Virus in Respiratory Secretions

Virus in Stool

Symptoms

Specific Antibody

Incubation Period

Time Course of Adenovirus Respiratory Infections

~~

Viremia **

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 21

DAYS

** in the immunosuppressed www.freelivedoctor.com

HERPESVIRUSESHERPESVIRUSES


They encode their own viral DNA polymerase, as well as other enzymes, such as thymidine kinase

Due to specificity and differences of these enzymes from that of the host, this has allowed development of targeted antivirals, such as acyclovir and ganciclovir

Terminal inverted repeats allow circularization. Replicate as a rolling circle, producing concatemeric DNA (multiple copies of the genome covalently linked end-to end)

Concatemers cleaved to yield genome-size pieces and packaged into an icosahedral nucleocapsid. Genome has long (L) and short (S) segments, assorted into 4 isomeric forms (isoschizomers) that can each be packaged

HERPES REPLICATION


HERPES REPLICONHERPES REPLICON


HERPEVIRUS GENOMESHERPEVIRUS GENOMES


POXVIRUSESPOXVIRUSES

200-300nm enveloped, brick-shaped viruslargest known virus family; core (c) is DNA


SMALLPOX HISTORYSMALLPOX HISTORY

The Pharaoh Ramses V (left) died of smallpox in 1157 B.C. The disease reached Europe in 710 A.D. and was transferred to America by Hernando Cortez in 1520 - 3.5 million Aztecs died in the next 2 years. In the cities of 18th century Europe, smallpox reached plague proportions and was a feared scourge - highly infectious. Five reigning European monarchs died from smallpox during the 18th century.www.freelivedoctor.com

Replication of Poxviruses


PARVOVIRUSESPARVOVIRUSES

Small (22nm) naked single stranded (SS) DNA viruses. There are two major subgroups: i) autonomous replicating and ii) dependoviruses. An example of the former is B19 which is the only significant agent of human disease.www.freelivedoctor.com

PARVOVIRUS REPLICATIONPARVOVIRUS REPLICATION

Both above subgroups replicate through a DNA strand intermediate, which is complimentary to the DNA strand in the parent virion.

Unique Replication Features:

Single strand has terminal hairpins formed by palindromic sequences.

As with other viruses with terminal repeats, intermediate DNA forms replicate through concatemers.


PARVOVIRUS DISEASESPARVOVIRUS DISEASES

Erythema infectiosum or "fifth exanthem", a self-limited febrile illness of children with a facial rash ("slapped cheek" syndrome)--usually ages 4-15 years. B19 is associated with "aplastic crisis" in anemia patients, and sickle-cell anemia patients. It can also lead to idiopathic red cell aplasia in AIDS patients.

In seronegative pregnant women it can cause hydrops fetalis, where an aborted fetus is delivered. Less often: rheumatoid arthritis in young adults or hepatitis in children.


SLAPPED-CHEEK SYNDROMESLAPPED-CHEEK SYNDROME


Diseases from B19 Infection

B19 Infection Antibody Excess Immune complexdeposition

Fifth Disease

B19 Infection Virus Excess+ hemolyticdisorder

Transient Aplastic Crisis

YY

YYYY

Y Y YY

Y

YY

Y

Y

Y YY


Diseases from B19 Infection

B19 Infection No -Antibody due to immunodeficiency

Red Cell Aplasia

B19 Infection Virus in Fetal Liver, Bone Marrow,of Fetus and Possibly Heart

Hydrops Fetalis or Congenital Red Cell Aplasia www.freelivedoctor.com

HUMAN PAPOVAVIRUSESHUMAN PAPOVAVIRUSES

Naked, icosahedral viruses (40-55 nm) with circular, ds DNA. So called from original 3 agents grouped in this family: papilloma, polyoma, and simian vacuolating agent (SV40). Now grouped into only two subfamilies: the larger sized Papillomaviruses (50% more DNA) and smaller Polyomaviruses.


PAPOVAVIRUS REPLICATIONPAPOVAVIRUS REPLICATION

Replicate in a circle from a single origin, by bi-directional fork (like a plasmid).

Early genes transcribed in one direction off one strand: late genes transcribed in opposite direction off other strand.

Early proteins (T Ag) are multifunctional, including late transcription in nucleus, and may also include either benign or malignant tumors.


HEPADNAVIRUSESHEPADNAVIRUSES

Virus is enveloped and known as Dane particle (45 nm), it contains HBV surface antigen; Core (22nm) (arrow) contains capsid HBc antigen. Also, a different ORF of the core encodes HBe, whose presence is associated with infectivity.


LATEST ON PRIONS ILATEST ON PRIONS I

Transmissible spongiform encephalopathies (TSEs) are not viruses or viroids; they are prions.

Examples of prions include: 1. Scrapie in sheep

2. Creutzfeldt-Jacob Disease (CJD) in humans

3. Bovine Spongiform Encephalopathy (BSE) or MadCow Disease in cattle. Following ingestion of beefby humans the disease is known as vCJD, which isa variant of CJD.

4. Gerstmann-Straussler-Scheinker syndrome (GSS) inhumans www.freelivedoctor.com

LATEST ON PRIONS IILATEST ON PRIONS II

The prion consists partly or entirely of a conformational isoform of the normal host protein PrPc. When the abnormal conformer is introduced into the organism it causes the conversion of the host PrPc into a likeness of itself. The physiological role of PrPc and the pathological mechanisms of neurodegeneration in prion diseases are still elusive.


PRION ProteinPRION Protein

Normal Folding Pattern of PrP

Alternate Folding Pattern of PrPSc


dna virus

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