Emerging Viruses Lecture4

Emerging Viruses

Origin of Viruses

Virus Evolution What are the selective forces that drive virus evolution? Viruses are the most successful life form in the planet. Despite minimal set of genes viral populations display spectacular diversity .The sources of this diversity are mutation, recombination, and selection. The selective forces working on viruses are imposed by the environment or the constrains of the viral genome and life cycle.

Replicating Viruses Produce Large Numbers of Mutant Genomes RNA viruses are copied with considerably less fidelity, error rates are high. DNA viruses tend to have low error rates during genome replication because of error-correcting DNA polymerases . Error rates are somewhat higher than that observed for the host genomes. DNA viruses that establish latent infections do not replicate their genomes extensively. As a result, diversity is reduced. Herpesviral genomes that establish long lived latent infection change at about the same rate as that of the host.

Possibilities for Variation Within Viral Genomes Can Be Astronomical For a 10kb RNA genome – 45,000 mutations. Deletions, recombination and reassortment add to this number. The conclusion is inescapable: virus evolution is relentless; new mutants will always arise and the possibilities literally are unimaginable.

Viruses exchange information Viruses exchange information by recombination or reassortment. Recombination occurs when the polymerase changes templates (copy choice) during replication (RNA viruses) or when nucleic acid segments are broken and rejoined (ds DNA viruses). Reassortment: Exchange of genetic information among genomic segments when cells are coinfected with segmented RNA viruses (orthomyxoviruses and reoviruses). Other Mechanisms Insertion of nonviral nucleic acids into the viral genome ( sequence independent recombination).

Evolution Is Constrained by the Fundamental Properties of Viruses Viral population frequently maintain quite stable “master” or consensus sequence, despite opportunities for extreme variation (HIV for example).

How stability is maintained: •

All viruses share fundamental characteristics that define and constrain them. Those that can function within the constrains survive.

• Genome size limits/ icosahedral capsids have a defined internal space • Proteins required for viral replication and interactions with cellular components • Viral proteins that overcome a broad spectrum of host defenses

Two general pathways for viral evolution •Viruses coevolve with their hosts so that both share a common fate; as the host prospers so does the virus. loss of the host results in loss of the virus. DNA viruses tend to follow this pathway. •Viruses have multiple host species. When one is compromised, the virus can replicate in another. RNA viruses tend to follow this pathway.

Emerging Viruses We define an emerging virus as one that either has newly appeared in the population or is rapidly expanding its range of hosts with a corresponding increase in detectable disease

The Source of “New” Viruses Are Strictly Limited to Three Possibilities Modern evolution of viruses Three possibilities for the origin of the “new” viruses 1. Mutant virus already existing in an infected host can be selected 2. A virus can enter a naïve population from an infected population of the same species 3. A virus can enter a naïve population from an entirely different infected species

Examples of Emerging Viruses Ecological, demographic, life-style changes

The General Interactions of Hosts and Viruses-hypothetical situations Resistant host

Evolving Intra Sp. Stable

Dead-end Inter Sp.

Complex Host –Virus Relationship

EEE, WEE

Dengue Fever Yellow Fever WNF

Other mammals and birds

Human Horses

Infectious Cycle of the Central European Tick-borne Encephalitis

Flavi

Rodents Can Play Critical Roles in the Introduction of”New” Viruses Hemorrhagic disease viruses Lassa – W.Af (f,p,e,h) Junin, Macupo-S.Am arenaviridae Hantaviruses – Bunyaviridae 3HFRS/4PS

Marburg – filoviridae (?) Ebola – filoviridae (?)

excertion

What Are the Important Factors That Influence Infiltration and Spread in a Given Population?

•Population density (direct/indirect contact, common water supply) •The critical population size ( isolation) •Clinical status ( babies, elderly, malnutrition) •Seasonal variation (Arbo/summer, Adeno, rhino/spring, corona,,RSV/winter)

•Other factors? -Lessons from accidental infections ( World war II :HBV contaminated vacc , 1955: Polio virus inactivated vacc. ,1950: Rabbit myxoma virus planned to kill rabbits in Australia)

Known Viruses Can Expand Their Niche Because of Changing Host Populations and Environment 1. Disease of modern sanitation (poliovirus in the early 20th century 2. Disease of exploration and colonization (lethal epidemics of measles and smallpox). Explosive epidemic spread due to viruses finding susceptible hosts in the larger population that have never been exposed (the evolving host-virus interaction).

3. Human disease resulting from genetic reassortment of viruses in animals (influenza A virus as an example). Influenza is the paradigm for a situation in which continued evolution of the virus in several host species is essential for its maintenance.

4. Human disease resulting from changing climate and animal. Zoonoses are often classic cases of emerging viruses that reflect our changing environment (hantavirus zoonotic infection, filaviruses, caliciviruses)

Poliovirus in the Early 20th Century Urbanization and Industrializataion

Known Viruses Can Expand Their Niche Because of Changing Host Populations and Environment Disease of exploration and colonization (lethal epidemics of measles and smallpox). Explosive epidemic spread due to viruses finding susceptible hosts in the larger population that have never been exposed (the evolving host-virus interaction).

Known Viruses Can Expand Their Niche Because of Changing Host Populations and Environment Human disease resulting from genetic reassortment of viruses in animals (influenza A virus as an example). Influenza is the paradigm for a situation in which continued evolution of the virus in several host species is essential for its maintenance.

Epidemiology Epidemics – Influenza A and B Antigenic drift Mutations in HA or NA New strain emerges Pandemics - Influenza A A new hemagglutinin and/or a new neuraminidase Antigenic shift New subtype emerges

Genetic Variations in Influenza Virus

A/H1N1

New strain PB2 PB1 PA HA NA NP M NS

>2 mutations HA or NA

A/England/10/80(H1N1)

→

PB2 PB1 PA HA NA NP M NS A/Paris/15/94(H1N1)

I - Antigenic drift Mutations (in A;B;C)-

PB2 PB1 PA HA NA NP M NS

PB2 PB1 PA HA NA NP M NS PB2 PB1 PA HA NA NP M NS

A/H2N2

New Subtype A/H2N1

II - Gene reassortmentonly in A - Antigenic shift

Resp19

Human Diseases Resulting From Genetic Reassortment of Viruses Antigenic shift: reassortment between human and non human virus in a nonhuman host cell. Antigenic drift: accumulation of mutations that facilitate evasion from the host immune system. Several hosts, continued evolution, new viruses emerge

1983

1997

Influenza Pandemic

1957-H2N2;1968-Hong-Kong;1977-Russian

Transitory Avian Influenza in humans- H5N1

H5N1 • An outbreak of Avian Influenza H5N1 occurred in Hong Kong in 1997 where 18 persons were infected of which 6 died. • The source of the virus was probably from infected chickens and the outbreak was eventually controlled by a mass slaughter of chickens in the territory. • All strains of the infecting virus were totally avian in origin and there was no evidence of reassortment. • However, the strains involved were highly virulent for their avian hosts. • 2002- highly pathogenic H5N1 in waterfowl, Hong Kong; 2003 - two families in Hong Kong; 2004 – poultry outbreak in China and 23 deaths out of 34 infected people in Thailand and Vietnam

Eradication of emerging new strain: Killing of millions of infected poultry

Genetic reassortment betwween avian and human influenza viruses taking place in the pig

Roles of pigs in interspecies transmission and adaptation of influenza viruses

-April 09 Outbreak H1N1

NA and M segments, closely related to Influenza viruses isolated from pigs in Euroasia and 6 segments from influenza viruses isolated from pigs from North America

Known Viruses Can Expand Their Niche Because of Changing Host Populations and Environment Human disease resulting from changing climate and animal populations( Zoonoses are often classic cases of emerging viruses that reflect our changing environment. (Hantavirus, Filoviruses, Caliciviruses, Flaviviruses)

Yellow Fever Virus: Humans Change the Pattern and Pay Price

Philadelphia Summer-fall 1793

SARS – GLOBAL DISTRIBUTION

Coronaviruses isolated from SARS

CLASSIFICATION Family: Coronaviridae, enveloped virions with long positive (+) RNA genome Genus: Coronavirus Groups: host range, antigenicity, gene organization 1 - mammalian (HCoV-229E) 2 - mammalian (HCoV-OC43) 3 - avian New group – SARS-HCoV (Tor2 and Urbani) Human infections: Respiratory diseases and gastroenteritis associated Animal infections: Livestock, ducks and domestic animals infectious bronchitis virus feline infectious peritonitis transmissible gastroenteritis virus others

Animal Origin – interspecies transmission SCoV-like viruses with 99.8% homology to SARSCoV were isolated from small wild animals in a retail market in China: • Himalayan palm civets - a culinary delicacy in Southern China • Raccoon-dogs • Ferret badgers Recently : from domestic cats

- The original natural SARS reservoir - not known yet Way of transmission: raising, slaughtering or preparing the creature for consumption (not eating) – Ab in 40% of people trading in wild animal markets

Current opinion: An ongoing transmission from animal to humans that have been occurring, but going undetected due to low virulence, until emerged a predominant genotype with high virulence

Where did the virus originate from? Animal Origin – interspecies transmission SCoV-like viruses with 99.8% homology to SARSCoV were isolated from small wild animals in a retail market in China: • Himalayan palm civets - a culinary delicacy in Southern China • Raccoon-dogs • Ferret badgers Recently : from domestic cats

- The original natural SARS reservoir - not known yet Way of transmission: raising, slaughtering or preparing the creature for consumption (not eating) – Ab in 40% of people trading in wild animal markets

Current opinion: An ongoing transmission from animal to humans that have been occurring, but going undetected due to low virulence, until emerged a predominant genotype with high virulence

Known Viruses Can Expand Their Host Range or Pathogenicity by Mutation or Recombination Host range jump from monkey to human rapid, multiple changes (the origin of HIV from a simian virus) Cat- to -dog host range change by two mutations: the canine parvovirus 1978-Feline panleukopenia virus

Human Immunodeficiency Virus (HIV) and Simian Immunodeficiency Virus (SIV) Phylogeny

Some Emergent Viruses Are Truly Novel 2. Discovery of new hepatitis viruses in blood supply by recombinant DNA technology (hepatitis C and G viruses) 3. Discovery through PCR (discovery of HHV8 by representational difference analysis)

Humans are constantly providing new ways to meet viruses

Humans Are Constantly Providing New Ways to Meet Viruses

What will be the next pandemic virus ? Ebola virus? Lassa virus? Hantaan Virus? Influenza Virus?

What can we do about emerging viruses? World wide public health measures •Vector management •Water and sewage management •Better nutrition •Global surveillance •Vaccines made available •Rapid diagnosis