Nov10 Lecture 20 Evolution

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Lecture 21Case study influenza virusand
Case study HIV/AIDS
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Today

• Learning from the past to predict the future of
  influenza
• The causes and consequences of HIV evolution
• The glycan shield and within-host and
  between-host evolution of HIV

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Global impact of flu

• Flu is a highly contagious respiratory illness
  which infects millions of people every year and
  kills hundreds of thousands
• Caused by influenza viruses (A, B, C)
• Estimated to infect 100 million people each year
  in the northern hemisphere alone
• Huge impacts on morbidity and mortality, but also
  economic impacts

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Global impact of flu

• Pandemics occurred in 1890, 1918, 1957, and 1968.
  The 1918 Spanish flu epidemic probably infected
  about 50 of the human population and represents
  the most intense culling of humans, ever.
• It is very likely that pandemic influenza will
  return
• Evolutionary tools can help fight currently
  circulating influenza, and possibly dampen the
  effects of future pandemic strains
• Antigenic drift versus antigenic shift

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What is influenza?

• There are 3 main types of influenza virus A, B,
  and C
• Well concentrate on influenza A, the most
  important from the human standpoint
• Negative-stranded RNA viruses with segmented
  genome
• 8 RNA segments encoding around 10 proteins

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What is influenza?

• 2 glycosylated proteins on the surface, HA
  (hemagglutinin) and NA (neuraminidase)
• HA and NA are involved in virus attachment and
  release from hosts cells
• They are the primary targets of the immune system
  in humans (and swine)
• Different strains of influenza are typically
  named for their HA and NA genes, eg. H1N1

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What is influenza?

• The virus is capable of generating a lot of
  genetic variability
• First, like other RNA viruses, the lack of
  proofreading and high error rate of the viral
  polymerase leads to high mutation rate.
• This high mutation rate, in turn, leads to a high
  substitution rate.
• (Substitutions are mutations that have become
  fixed through genetic drift or natural selection)
• When these substitutions occur in antigenic
  epitopes, they can lead to escape mutants
  (antigenic drift)

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What is influenza?

• The segmented nature of the influenza genome
  leads to another, more dramatic source of
  variability
• Reassortment can occur when one host is
  co-infected with two different strains, and the
  progeny viruses get some gene segments from one
  parent and some from another
• For example, if you were infected simultaneously
  with both H1N1 and H3N2, you might generate an
  H1N2 virus that could infect someone else and
  start a new epidemic

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Where does flu come from?

• Reassortment gets particularly ugly when HA
  and/or NA genes that are new to the human
  population are introduced
• There are 15 HA subtypes lurking in the gene pool
  of influenza that infects wild birds (H1-H15)
• Birds are the reservoir of human influenza, the
  source from which new viruses periodically emerge
  via zoonosis
• Importation of a variant to which few or no
  humans have prior immunity (antigenic shift) is
  the cause of the periodic pandemics

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Where does flu come from?

• Since pigs can be infected with both avian and
  human influenza, and various reassortants have
  been recovered from pigs, it has been suggested
  that pigs might play the role of intermediary in
  the generation of reassortant pandemic strains
• In 1979, for example, an avian influenza A began
  infecting swine in Northern Europe. This lineage
  has since clearly mixed with locally circulating
  human lineages, and has picked up human H and N2
  HA and NA segment via reassortment

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Where does flu come from?

• 1997, it became clear that avian influenza could
  also jump directly from birds into humans
• The Hong Kong 1997 variant was an avian H5N1
  virus that infected 18 people and killed 6
• Luckily, the virus was poorly transmissible in
  humans (if at all)
• What would happen if someone got infected with
  avian H5N1 from their chicken, and also human
  H1N1 from their co-worker?

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Where does flu come from?

• 1918 Spanish flu probably infected about 1
  billion of the worlds 1.8 billion people, and
  led to the death of perhaps 50 million
• Most deaths occurred in an 8-week window,
  October-November 1918
• Most deaths due to complications like pneumonia,
  dehydration
• Unusual pattern of mortality, with healthy
  adults, 20-25, hardest hit

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Where does flu come from?
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Where does flu come from?
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Where does flu come from?
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Where does flu come from?

• Painstaking work has been done to reconstruct the
  1918 variant from archival specimens
• No clear virulence factor was initially
  discovered
• Recombination (as opposed to reassortment) was
  proposed as a solution, but thats wrong

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Where does flu come from?

• Recent structural studies of the HA protein of
  the 1918 virus revealed that, while maintaining
  many features of an avian virus, the structure of
  the HA allows it to bind to human cells without
  any trouble
• So maybe the 1918 virus was the perfect storm
  in the sense that it represented a totally new
  gene, for which there was no standing immunity.
  But it could nevertheless replicate and transmit
  efficiently

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Where does flu come from?

• Its still not clear whether the virus jumped
  directly from birds or not
• However, the children of 1918 may have been more
  accurate than anyone could have imagined
• Further research should help answer remaining
  questions and inform surveillance and control
  measures

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Molecular clocks and natural selection
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Molecular clocks and natural selection
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Molecular clocks and natural selection
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Molecular clocks and natural selection
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Predicting the future of influenza

• What is the expectation in the ratio of Dn/Ds if
  all changes are neutral?
• What if changes to amino acids tend to be
  unfavorable?
• What if changes to amino acids are favored?
• Dn/Ds 1 neutrality
• Dn/Ds lt 1 negative selection (a.k.a. purifying
  selection
• Dn/Ds gt 1 positive selection

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• Antigenic drfit due to mutations in the
  hemagglutinn gene necessitates frequent
  replacement of influenza A strains in the human
  vaccine
• At least 18 of the 329 H3 HA1 codons have been
  under positive selection to change in the past
• These showed a significant excess of nucleotide
  substitutions that result in amino acid
  replacements.
• If the selective pressure on these was to evade
  immune responses of the host, then viruses with
  mutations at these codons should have been more
  fit
• If true, could these patterns be used to predict
  which currently circulating strains will have
  highest fitness?

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• Tested predictions retrospectively
• They defined fitness as follows if one viral
  strain is more closely related to future lineages
  than another strain, regardless of virulence, it
  is more fit
• Hence the goal of this work was not the same as
  predicting the epidemic strain for the next year,
  or predicting antigenic shift events

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• Bush et al. used patterns of positive selection
  to predict trunk lineages in influenza A
• 18 codons in the HA gene of subtype H3 appear to
  be under positive selection
• Retrospective tests showed that lineages
  undergoing the greatest number of changes in
  those codons were the progenitors of future H3
  lineages in 9 of 11 recent flu seasons
• Could help identify most fit extant strains
  that arise due to antigenic drift

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• The positive selection method predicted correctly
  9 years out of 11
• There was a significant overlap between the
  positively selected sites and the codons in or
  near antibody combining sites and the sialic acid
  receptor binding site
• How could these results be used to control
  influenza?

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• Understanding HIV evolution crucial for
• Reconstructing its origin
• Deciphering its interaction with the immune
  system
• Developing effective control strategies like drug
  therapy and vaccines

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• HIV can infect a variety of cell types, but AIDS
  results from depletion of CD4 T-helper lymphcyte
  cells
• The env gene codes from the glycoproteins of the
  outer envelope of the virus
• The gag (group-specific antigen) gene encodes the
  components of the inner capsid protein
• The pol (polymerase) gene codes for the enzymes,
  including reverse transcriptase, that are used in
  viral replication
• Which gene evolves the fastest?

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• Recombination plays a large role at all levels of
  HIV diversity
• Including the origin of SIVcpz

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• Evolution within and among hosts
• Bottlenecks at transmission reduce diversity
• But could the bottleneck have an adaptive
  explanation?
• Phylogenies revealed that HIV continually
  replicates even when undetectable. How?

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• Heterosexual transmission accounts for most HIV
  infections worldwide, so understanding its ground
  rules is very important
• Frequency of infection per coital act in less
  than 0.5, so its pretty inefficient
• Why?
• Low amounts of virus?
• Restricted access to target cells?
• Selective transmission of a minority of variants?
• Selective outgrowth of minority of variants?
• Mother-to-infant transmission studies first
  showed that a restricted subset of viruses was
  observed soon after infection
• Studies of sexual transmission have suggested
  that homogeneous, macrophage-trophic strains
  generally establish infection

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• Derdeyn et al systematically examined the
  properties of viruses transmitted in a series of
  FTM and MTF transmission pairs
• Large cohort of HIV-discordant cohabiting couples
  in Zambia (one has HIV, one doesnt, at start)
• Eight couples out of gt1000 showed HIV
  transmission
• Blood samples collected simultaneously from both
  couples with a few months of transmission.

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• Recipient viruses were monophyletic, nested
  within donor variation
• They tended to encode compact, glycan-restricted
  envelope glycoproteins
• This suggest that variants within a donor host
  that have not evolved changes in their env genes
  that code for a glycan shield are either
  transmitted more effectively, or outcompete other
  variants when they get transmit to a new host?
• These variants were uniquely sensitive to
  neutralization by antibody from the transmitting
  partner
• The exposure of neutralizing epitopes, which are
  lost in chronis infection because of ongoing
  immune escape mutation/selection, appears to be
  favored in the newly infected host
• Implications for vaccine design?

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The war within the host
Elimination of the officers leaves entire armies
wandering aimlessly, and any invasion becomes
successful
The officers normally give orders to release
mustard gas and send troops into battle
antibodies
Killer T-cells
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The war within the host

• Heterosexual transmission accounts for most HIV
  infections worldwide, so understanding its ground
  rules is very important
• Frequency of infection per coital act in less
  than 0.5, so its pretty inefficient
• Why?
• Low amounts of virus?
• Restricted access to target cells?
• Selective transmission of a minority of variants?
• Selective outgrowth of minority of variants?

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The war within the host

• Derdeyn et al systematically examined the
  properties of viruses transmitted in a series of
  FTM and MTF transmission pairs
• Large cohort of HIV-discordant cohabiting couples
  in Zambia (one has HIV, one doesnt, at start)
• Eight couples out of gt1000 showed HIV
  transmission
• Blood samples collected simultaneously from both
  couples with a few months of transmission.

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The war within the host
MALE (newly infected) FEMALE (old infection)
Only one of the diverse strains in the infected
host ever made it to the new host WHY?
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The war within the host

• Variants without a sugar shield are either
  transmitted more effectively, or outcompete other
  variants when they transmit to a new host
• Transmitted variants appear to be easier to
  control with antibodies
• Implications for vaccine design?

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The war within the host
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The war within the host