Download Nov10 Lecture 20 Evolution & vaccines

Lecture 21
Case study: influenza virus
and
Case study: HIV/AIDS
Today:
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Learning from the past to predict the future of influenza
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The causes and consequences of HIV evolution
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The “glycan shield” and within-host and between-host
evolution of HIV
Global impact of flu
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Flu is a highly contagious respiratory illness which
infects millions of people every year and kills
hundreds of thousands
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Caused by influenza viruses (A, B, C)
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Estimated to infect 100 million people each year in
the northern hemisphere alone
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Huge impacts on morbidity and mortality, but also
economic impacts
Global impact of flu
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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.
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It is very likely that pandemic influenza will return
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Evolutionary tools can help fight currently
circulating influenza, and possibly dampen the
effects of future pandemic strains
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Antigenic drift versus antigenic shift
What is influenza?
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There are 3 main types of influenza virus: A, B,
and C
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We’ll concentrate on influenza A, the most
important from the human standpoint
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Negative-stranded RNA viruses with segmented
genome
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8 RNA segments encoding around 10 proteins
What is influenza?
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2 glycosylated proteins on the
surface, HA (hemagglutinin)
and NA (neuraminidase)
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HA and NA are involved in
virus attachment and release
from hosts cells
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They are the primary targets of
the immune system in humans
(and swine)
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Different strains of influenza
are typically named for their
HA and NA genes, eg. “H1N1”
What is influenza?
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The virus is capable of generating a
lot of genetic variability
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First, like other RNA viruses, the
lack of proofreading and high error
rate of the viral polymerase leads to
high mutation rate.
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This high mutation rate, in turn,
leads to a high substitution rate.
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(Substitutions are mutations that
have become fixed through genetic
drift or natural selection)
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When these substitutions occur in
antigenic epitopes, they can lead to
escape mutants (antigenic drift)
What is influenza?
•
The segmented nature of the
influenza genome leads to another,
more dramatic source of variability
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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
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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
Where does flu come from?
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Reassortment gets particularly ugly
when HA and/or NA genes that are
new to the human population are
introduced
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There are 15 HA subtypes lurking in
the gene pool of influenza that
infects wild birds (H1-H15)
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Birds are the reservoir of human
influenza, the source from which
new viruses periodically emerge via
zoonosis
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Importation of a variant to which few
or no humans have prior immunity
(antigenic shift) is the cause of the
periodic pandemics
Where does flu come from?
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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
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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
Where does flu come from?
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1997, it became clear that avian influenza could
also jump directly from birds into humans
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The Hong Kong 1997 variant was an avian H5N1
virus that infected 18 people and killed 6
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Luckily, the virus was poorly transmissible in
humans (if at all)
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What would happen if someone got infected with
avian H5N1 from their chicken, and also human
H1N1 from their co-worker?
Where does flu come from?
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1918 Spanish flu probably infected about 1 billion
of the world’s 1.8 billion people, and led to the
death of perhaps 50 million
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Most deaths occurred in an 8-week window,
October-November 1918
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Most deaths due to complications like pneumonia,
dehydration
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Unusual pattern of mortality, with healthy adults,
20-25, hardest hit
Where does flu come from?
Where does flu come from?
Where does flu come from?
Where does flu come from?
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Painstaking work has been done to reconstruct
the 1918 variant from archival specimens
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No clear virulence factor was initially discovered
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Recombination (as opposed to reassortment) was
proposed as a solution, but that’s wrong
Where does flu come from?
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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
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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
Where does flu come from?
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It’s still not clear whether the virus jumped directly
from birds or not
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However, the children of 1918 may have been
more accurate than anyone could have imagined
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Further research should help answer remaining
questions and inform surveillance and control
measures
Molecular clocks and natural selection
Molecular clocks and natural selection
Molecular clocks and natural selection
Molecular clocks and natural selection
Predicting the future of influenza
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What is the expectation in the ratio of Dn/Ds if all
changes are neutral?
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What if changes to amino acids tend to be
unfavorable?
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What if changes to amino acids are favored?
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Dn/Ds = 1: neutrality
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Dn/Ds < 1: negative selection (a.k.a. purifying
selection
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Dn/Ds > 1: positive selection
•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?
•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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•
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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
•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?
Understanding HIV evolution crucial for…
•Reconstructing its origin
•Deciphering its interaction with the immune system
•Developing effective control strategies like drug therapy
and vaccines
•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?
•Recombination plays a large role at all levels of HIV
diversity
•Including the origin of SIVcpz…
•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?
•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 it’s
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
•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 doesn’t, at start)
•Eight couples out of >1000 showed HIV transmission
•Blood samples collected simultaneously from both couples with
a few months of transmission….
•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?
The war within the host
The officers normally
give orders to
release mustard gas
and send troops into
battle
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TIFF (Uncompressed) decompressor
are needed to see this picture.
antibodies
Elimination of the
officers leaves entire
armies wandering
aimlessly, and any
invasion becomes
successful
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TIFF (Uncompressed) decompressor
are needed to see this picture.
Killer T-cells
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 it’s
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?
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 doesn’t, at start)
•Eight couples out of >1000 showed HIV transmission
•Blood samples collected simultaneously from both couples with
a few months of transmission….
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?
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?
The war within the host
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
The war within the host
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.