Evolutionary Analysis Chapter 1
CHAPTER 1: A CASE FOR EVOLUTIOARY THINKING: UNDERSTANDING
HIV
• Why study evolution?
o Charles Darwin (1859) wrote “Light will be thrown” in
his book “On the origin of man and his history”
o Theodosius Dobzhansky (1873) said “Nothing in biology
makes sense”, “except in the light of evolution”
§ Architect of modern view of evolution
§ Evolutionary biology is the conceptual
foundation for all of life science
o Its tools and techniques offer crucial insights into
matters of life and death
o Evolution of HIV (Human Immunodeficiency Virus)
which causes AIDS (Acquired Immune Deficiency
Syndrome)
§ Multiple therapies transformed HIV from fatal
to treatable but still may fail.
o HIV is an emerging pathogen which evolves drug
resistance and deadly.
o AIDS is among 10 leading causes of death worldwide
(Lopez et al. 2006; WHO 2008)
As a case study, HIV will demonstrate how evolutionary biologists
study adaptation and diversity.
1.1 THE NATURAL HISTORY OF HIV EPEDEMIC
• In 1981, AIDS recognized in US with rare forms of pneumonia
and cancer among male-male sex.
o HIV was responsible virus
• Many were optimistic about the prospects for containing HIV
since vaccines and antibiotics control infectious diseases.
o In 1980, Smallpox was eradicated.
o Margaret Heckler – US Sec. of Health and Human
Services (1984), predicted that vaccines for AIDS was
ready for testing in two years but actual events played
out.
• HIV infected 65 million people (UNAIDS 2010, 2012a)
o 30 million died in AIDS which causes 3.1% of all deaths
worldwide
o AIDS is responsible for fewer deaths than the following
disease:
§ Heart disease (12.8%)
§ Strokes (10.8%)
§ Lower respiratory tract infections (6.1%) -
Common cause of death among elders
• 2008 – HIV most devastation in sub-Saharan African which
1 out of 20 adults living with it. Switzerland with 26% of
infected adult followed by the following countries:
o Botswana – 24%
o Lesotho – 23%
o South Africa – 18%
§ Life expectancy at birth dropped below
50
• 2012 – Annual rate of new infections in sub-Saharan Africa
falling over the decade as well as global rate of new
infections.
• 2008 – Rates of infected adults in developed countries
o Western and central Europe – 0.3%
o Canada – 0.4%
o US – 0.6%
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• 2005 to 2008 – Rates of among infected men who have sex
with men
o London – 12%
o NY City – 18%
o San Francisco – 24%
• 2008 – Rates among injection drug users
o France – 12%
o Canada – 13%
o US – 16%
HOW DOES HIV SPREAD, AND HOW CAN IT BE SLOWED?
• HIV infection start when bodily fluid carries the virus from
infected person onto mucous membrane or bloodstream
of uninfected person.
o Travels via semen, vaginal and rectal secretions,
blood and breastmilk.
o Pass during sexual intercourse, oral sex, needle
sharing, transfusion with contaminated blood,
other unsafe medical procedures, childbirth and
breastfeeding.
• Common cause of HIV infection across the globe
o In sub-Saharan Africa and south and southeast
part of Asia, heterosexual was common mode of
transmission.
o In Europe and America, Male-male sex and
needle sharing among injection drug users have
predominated.
o In Victoria, Australia, anal intercourse without
condom is dangerous which was 60% chances to
acquire the virus.
• List of medical interventions that reduces the rate of HIV
o Antiviral drugs lower the risk that infected
mother will pass the virus to the infant about
40%.
§ Effective in reducing transmission
among male-male sex
o Circumcision reduces the risk of men to contract
HIV about half.
o Antiviral vaginal gels are beneficial for women.
o Using of condom reduces the risk for about 80%
and more. Also, regularly testing.
§ In Uganda, it reduces the AIDS
epidemic.
o In US, over 4000 HIV negative men who have sex
with men was offered extensive counselling in
experimental group and conventional
counselling to the control group hoping to lower
the risky sexual behavior. However, rates were
not statistically distinguishable which was
disappointing.
• In US, after the rate was fell in mid-1980s to early 1990s
among male–male sex, new infections have been rising
steadily.
• Long-term drug therapies which transformed HIV into
manageable chronic illness, prompted an increase in sexual
behavior.
WHAT IS HIV?
• Intracellular parasites incapable of reproducing its own
which invades cell in human immune system.
Evolutionary Analysis Chapter 1
o Hijacks the enzymatic machinery, chemical
materials and energy of the host cells to make
copies of itself.
• Lifecycle of HIV (Extracellular Phase or infectious phase)
o Virus moves from host cell among other host
cells.
o Virion or virus particle is the extracellular form of
virus
• Lifecycle of HIV (Intracellular Phase or Replication phase)
o Virus replicates
• Replication Phase
o HIV latch onto two proteins (a. CD4 and b.
coreceptor) on the surface of host cell.
§ Fusion of virion’s envelope with host
cell and spills the contents of virion to
cell which contains:
• Virus genome – two copies of
ssRNA molecules
• Two viral enzymes: reverse
transcriptase – transcribes
virus genome to DNA and
integrase – splices DNA
genome into the genome of
host cell
o Once the HIV genome was infiltrated to host cell’s
DNA, host cell’s RNA polymerase transcribes the
viral genome into viral mRNA.
§ Host cell’s ribosomes synthesize viral
proteins.
§ Assembly of new virions in membrane
§ Virions bud off into bloodstream or
other body fluid.
§ Inside the new virions, HIV’s protease
enzyme cleaves precursors of various
viral protein into functional forms,
allowing virions to mature
§ New virions are now ready to invade
new cells in the same host or move to
another host cells
• HIV, and viral disease are difficult to treats since it has
enzymatic machinery – polymerases, ribosomes and tRNAs.
o Antiviral therapies target reverse transcriptase
and integrase of virus.
HOW DOES THE IMMUNE SYSTEM REACT TO HIV?
• Immune system fight HIV by combatting another viral
invader.
• Sentinels or dendritic cells patrol vulnerable tissues
(digestive and reproductive tracts).
a. Dendritic cells capture the virus.
b. Travels to a lymph mode or lymphoid tissue and
presents bits of virus’s proteins to specialized WBC
called naive helper T cells.
c. Helper T cells activates; grows, divides and produce
daughter cells called effector helper T cells.
• Naive helper T cells carries highly variable T-cell receptor
• Effector helper T cells, issue commands by cytokines, which
help mobilize a variety of immune cells to join fight.
o Induce B cells to mature into plasma cells which
produce antibodies that bind invading virions and
eliminate
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o Activate killer T cells which destroy infected host
cells
o Recruit microphages which destroy virus particles
or kill infected cells.
• Effector helper T cells die within a week, but few survive and
become memory helper T cells.
o If the same pathogen invades again, memory cells
produce a new population of effector helper T
cells.
HOW DOES HIV CAUSE AIDS?
• HIV latch into two proteins (CD4 and Coreceptors) into host
cell’s surface,
• Different strains of HIV exploit different coreceptors but
most strains responsible for new infections use protein
called CCR5.
• Membranes carry CD4 and CCR5 are vulnerable to HIV
which includes microphage, effector helper T cells and
memory helper T cells.
• HIV infection can be monitored by measuring the
concentration of HIV virions in the patient’s bloodstream
and CD4 T cells in the patients’ bloodstream and lymphoid
tissues associated with mucous membranes in the gut.
• Acute Phase
o HIV virions enter to host’s body and replicate.
o Concentration of virions in blood climbs steeply
o Concentration of CD4 T cells plummet– especially
in lymphoid tissue of gut
o Shows general symptoms of infections
o Ends when viral replication slows and the
concentration of virions in bloodstream drops.
o Host’s CD4 T cell counts recover
• Chronic Phase
o Patient has usually few symptoms
o HIV continue to replicate
o Concentration of virions in blood may stabilize
and eventually rises again
o Concentration of CD4 cells fall.
• AIDS Phase
o Begins when concentration of CD4 T cells in blood
drops below 200 cells per cubic millimeter.
o Patient’s immune system collapse and can no
longer fend off virus, bacteria and fungi.
o Without anti-HIV drug therapy, patients with AIDS
expect to live < three years
• HIV infection to AIDS
a. HIV attacks CD4 T cells in gut which initiates vicious
cycle – [destroy helper T cells and damage the tissue in
gut (provide barriers between gut bacteria and
bloodstream)
b. Translocation of bacteria and their products from gut
to blood. – [triggers high level of immune activation
c. Activation of immune system
I. Induces B cells and T cells to proliferate
NOTE: The immune system’s best effort to douse the HIV infection
just add fuel to the fire
• Patient’s Lymph node – major battleground between HIV
and immune system
o Place where naïve T cells are activated
Evolutionary Analysis Chapter 1
• Chronic infection and inflammations damage the lymph
nodes irreversibly and exhaust the immune system’s
capacity to generate T cells.
• As T cells concentration fall, immune systems lose its ability
to fight pathogens which results to AIDS
• How HIV stopped before it leads to AIDS?
o Azidothymidine or AZT – first drug (1987) to
prevent virus from replicating
1.2 WHY DOES HIV THERAPHY USING JUST ONE DRUG ULTIMATELY
FAIL?
• Researches look for drugs that inhibit enzymes that are
special to virus and crucial to its life cycle.
• In HIV, potential targets are virus’s protease, integrase, and
reverse transcriptase.
• AZT is the first drug approved to fight HIV which interferes
reverse transcriptase.
• Reverse Transcriptase
o Enzyme which use the virus’s RNA as a template
to construct complementary strand of viral DNA.
o Makes the DNA with nucleotide from host cells.
• AZT or Azidothymidine
o Stops reverse transcriptase
o Chemical structure is same to normal nucleotide
thymidine which fools reverse transcriptase into
picking it up and incorporating into growing DNA
strand.
• Difference between AZT and normal thymidine
o Thymidine has –OH while AZT has azide group (–
N3)
o The hydroxyl that AZT lacks is where reverse
transcriptase would attach the next nucleotide to
the growing DNA.
§ RT stuck which unable to add more
nucleotides
• AZT interrupts the pathway to new viral proteins a new
virion
o Halting the loss T cells in AIDS patients.
o Side effect: fools’ patient’s own DNA polymerase
which interrupts DNA synthesis,
• In 1989, patients stopped responding to treatment.
DOES AZT ALTER THE PATIENTS PHYSIOLOGY?
• AZT lose it effectiveness in two ways:
a. Patients own cellular physiology could change
- After AZT enters to the cell, it has to be phosphorylated by
the cell’s own thymidine kinase enzyme to become
biologically active.
- Long term exposure to AZT causes a cell to make less
thymidine kinase
• Patrick Hoggard and collogues (2001), tested hypothesis by
periodically checking the concentrations of phosphorylated
AZT in a group of patients taking the same dose.
o Data refuted the hypothesis and so the
concentrations of phosphorylated AZT did not
change over time.
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DOES AZT ALTER THE POPULATION OF VIRIONS LIVING IN THE
PATIENT?
• AZT lose it effectiveness in two ways:
b. The population of virions inside the patients could
change so the virions themselves would be resistant
to disruption by AZT.
• Brendan Larder and colleagues (1989) find out whether the
population of virions becomes resistant to AZT over time.
o Took sample of HIV from patients and cultured I
petri disk
o Curve falls show how rapidly HIV’s ability to
replicate is curbed by increasing concentrations
of AZT
o After two months, virions were still susceptible to
AZT.
o At moderate concentration, virions lost their
ability to replicate.
o After 11 months, virions were partially resistant.
It could be stopped but needed 10 times as much
as AZT.
o After 20 moths, virions were completely
unaffected.
o Population of virions changes to become resistant
to AZT –populations evolve.
o HIV evolve within six months of taking AZT.
WHAT MAKES HIV RESISTANT TO AZT?
• HIV capable of replicating in the presence of AZT
o Solution: modify the virus’s reverse transcriptase
to avoid inserting AZT molecules into growing
DNA.
• Exposed large amount of HIV virions to mutagenic chemical
or ionizing radiation
o Generate strains of HIV with altered nucleotide
sequences
o Thus, altered amino acid sequences in their
protein.
• Generate enough mutant
o Can carry few changes in active site of RT
molecules
§ Recognizes nucleotides, adds them to
growing DNA and correct mistakes
• If one RT with altered binding site were less likely to mistake
AZT for the normal nucleotide, or remove AZT after
insertion, then mutant HIV would continue to replicate in
the presence of drug.
• Treatment of mutant virions with AZT, HIV strains unable to
replicate in presence of AZT would decline in numbers.
• Viral strains preset late in treatment were genetically
different from viral strains before treatment in the same
host
o Mutations with AZT were often same from
patient–patient and cause AA changes in RT
active sites.
• Altered RT were still pick AZT and insert them from growing
DNA strand but they are more likely remove AZT and
therefore continue to build DNA copy.
• RTs are prone to mistakes
o Half of DNA transcripts contains one error–one
mutation– in nucleotide sequence.
Evolutionary Analysis Chapter 1
o Single strains of HIV produce large number of RT
variants in every host which then improve RT
ability to recognize and remove AZT
• AZT suppressed HIV variants, but still, resistant mutant will
still able to synthesize DNA and produce virions.
• As the resistant of virions propagate and the nonresistant
virions fail, the fraction of the virions in the patient’s body
that are resistant to AZT increases over time.
• Evolution by natural selection
o Process changes over time in the composition of the
viral population
EVOLUTION BY NATURAL SELECTION
a. Replication errors produce mutation in reverse transcriptase
gene. Virions carrying different RT produce RT enzyme which
vary resistant to AZT.
b. AZT resistance is heritable
c. Some virions are better to survive and reproduce during
treatment with AZT
d. Virions persist in the presence of AZT are the one with mutation
in RT gene which confer resistance.
• Virions resistant to AZT comprise a large fraction of
population; virions susceptible to AZT become rare.
• Evolution by natural selection are automatic consequence
of heritable differences in replication.
UNDERSTANDING EVOLUTION HELPS RESEARCHERS DESIGN BETTER
THERAPIES
• Categories of drug used to disrupt HIV’s life cycle
o Coreceptor inhibitors bar HIV from entering to host
cell by preventing them to latch in host cell’s CCR5
molecules.
o Fusion inhibitors bar HIV from entering to host cells by
interfering with HIV’s gp120 or gp41 protein.
o RT inhibitors – inhibit RT by mimicking the normal
blocks of DNA and inhibit RT by interfering with
enzymes active site.
o Integrase inhibitors blocks HIV’s integrase from
inserting HIV’s DNA into host of genome which
prevent transcription of new viral RNAs.
o Protease inhibitors prevents HIV’s protease from
cleaving viral precursor proteins to produce mature
components of virions.
• Single drug
o Outcomes same as AZT as host quickly evolves
resistance
o Few mutations for targeted viral protein can render
the virus resistant
o High mutation, short generation time and large
population size, HIV generates many mutant genomes
that variants with crucial combination of mutations
are likely to be present much of the time.
• Increase number of mutations in virion genome to render
virion resistant. More resistant lower the probability that
they will occur in a single virion.
• Reduce genetic variation for resistance
o Without genetic variations, the population cannot
evolve.
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o Raised number of mutations by using two or more
drugs.
• Treatment cocktails using combination of drugs
o Robert Murphy and colleagues (2008) used two
RT inhibitors and protease inhibitor in viral loads
of 100 patients.
§ 7 years later, 61 patients still
participating and 58 had viral loads
under 50 copies per mL of blood– low
enough to undetectable.
• Highly Active Antiretroviral Therapy or HAART improved
patient survival but it does not cure HIV infection.
o A reservoir of viable HIV genome remains in the
body, hidden in WBC and other tissue.
o When patient go off HAART, viral loads climb
rapidly.
THE EVOLUTION OF HIV STRAINS RESISTANT TO MULTIPLE DRUG
• Patient with high resistant strains of HIV face a higher risk
of death (Hogg et al. 2006)
• Some patients have the bad luck to become infected with
HIV strains that are already drug resistant (Johnson et al.
2008)
• Harrigan and colleagues (2005) calculate the percentage of
prescription refills each patient picked up.
o Hazard ration is the fraction of patients in a given
adherence category who evolved resistant HIV
divided by the fraction of patient in 0 to 20% refill
category who evolved resistant HIV.
• Patient fail to take all their prescribed doses causes side
effects
o Murphy’s (2008) study were changes body fat
distribution, liver damage, elevated cholesterol,
diarrhea and joint pain.
1.3 ARE HUMAN POPULATIONS EVEOLVING AS A RESULT OF THE HIV
PANDEMIC?
• For a population to evolve, it must be harbor genetic
differences
A MISSING CORECEPTO
• In 1996, researchers identified the cell surface protein CCR5
an important coreceptor for HIV
• Rong Liu and coworkers (1996) and Michael Samson and
associates (1996), guessed that resistant individuals might
have unusual forms of CCR5 that thwart HIV’s entry into
host cells.
o Lui and colleagues examined CCR5 from two
individual who exposed to HIV but remained
uninfected.
o Subjects was homozygotes for a mutant form of
gene and one of samson’s subjects was a
heterozygote.
o Reason: mutant form is distinguished by a 32–
base-pair deletion in a normal sequence of DNA –
Δ 32 allele
• Δ 32 allele confers strong protection against HIV which are
present at a relative high frequency of 9% in Europeans, but
completely absent among the individuals of Asians or
African descent
Evolutionary Analysis Chapter 1
o CCR5- Δ32 allele is common in northen Europe
and declines dramatically toward both south and
the east.
o Common in a part of the world where HIV is rare
GENETIC VARIATION FOR HIV RESISTANCE IN AFRICAN
POPULATIONS
• The most common allele of the gene for CD4 contains the
nucleotide C at position 868
o Alternative version called C868T has nucleotide T
resulting in substitution of the amino acid
tryptophan for arginine
o With a frequency of over 15% are common among
Kenyans.
o In Kenyans, research had undergone. 29 has
genotype CC and 16 had genotype CT.
§ The women with genotype CT
contracted HIV significantly more
quickly.
• African populations harbor heritable variation for
resistance to HIV
o Human populations in Africa are likely evolving in
response to mortality imposed by HIV
A MISSING PROTECTIVE ALLELE
• Retrocyclin is protein vertebrate cells that block stages of
retroviral life cycle.
o Human version of protein called theta defensin
which discovered in rhesus macaque and found in
old world monkeys, lesser apes and orangutan.
§ Small, circular proteins made by joining
two copies of a smaller linear precursor
• Alexander Cole and colleagues (2002) synthesized
retrocyclin and showed that it protects cultured human
CD4+ T cells from HIV infection.
o Our body could make retrocyclin to fight the virus
• Simple back-mutation, involving two nucleotide
substitutions would restore retrocyclin gene to its orginal
sequences, would allow us to make proteins.
PRACTICAL APPLICATIONS
• CCR5- Δ32 homozygotes– lack functional CCR5, suffer few
ill effects, and are resistant to sexually transmitted strains
of HIV– suggest antiretroviral therapy
o Used of rugs that bind to CCR5 and stop HIV from
latching into its coreceptor
A. MARAVIROC – CCR5 blocked
B. RETROCYCLIN RC-101 – used as vaginal microbicide that
could help block sexual transmission of HIV.
AN UNRESOLVED MYSTERY
WHY CCR5- Δ32 ALLELE COMMON IN EUROPE?
• Samson and coworkers (1996) suggest two general
explanation:
o Favored by natural selection in Europe population
o Allele could have risen to high frequency by
chance– genetic drift
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1.4 WHERE DID HIV COME FROM?
LOUSIANA V. RICHARD J. SCHMIDT
• Nurse Janet Trahan had a relationship with Dr. Richard
Schmidt
o She was his romantic partner during 10-year affair
o She was his patient and ended up this affair but
continued as Schmidt’s patient and colleague
• After breakup, Trahan accepted Schmidt offer to visit her
apartment to administer regular vitamin injection.
o Within a few weeks, Trahan have a symptom of
viral infection and tested positive after a few
weeks.
• THEORY: Schmidt instructed his nurse to draw extra blood
from an HIV- positive patient then intentionally injected the
infected blood into Trahan.
• The local district attorney’s office prosecuted Schmidt for
second attempted murder.
RECONSTRUCTING EVOLUTIONARY HISTORY
• HIV high mutation rate generates genetic variation.
• Evolutionary Tree
o Summarize the HIV’s history of diversification
within a patient
o Each split represents the generation of new
variant; the original variant continues on one
branch and the novel form continues on the
other.
o Branch tips represent different living or extinct
variants.
o Lineage have common ancestor.
§ Variants sharing more recent common
ancestor are more likely related to each
other
• Raj Shankarappa and colleague (1999) estimated the
relationship among variants by comparing its nucleotide
sequence in their genes.
o Principle: arrange the sequence and order of
branching so that less divergent sequence are on
neighboring branches.
• Each time an HIV virion moves from one host to another to
establish a new infection become roots of a new
evolutionary tree– chain of transmission.
EVOLUTION AS WITNESS FOR THE PROSECUTION
• Schmidt’s patient and Trahan were consecutive links in
chain of transmission.
• If Schmidt’s is innocent, then Trahan likely contracted HIV
from someone other than Schmidt’s patient. HIV from
Schmidt’s patient and Trahan are not closely related.
• If Schmidt’s is guilty, then evolutionary tree constructed will
show his patient’s HIV and Trahan’s HIV is closely related.
• RESULT: Virus from Schmidt’s patients and from Trahan are
closest relatives.
o Trahan viruses arise within the patient of
Schmidt.
o It is important that this tree, does not prove
Schmidt’s guilt which perhaps Trahan contracted
HIV from Schmidt’s patient without his
involvement.
Evolutionary Analysis Chapter 1
• Totality of evidence convince the jury that Schmidt’s was
guilty and now serving 50 years at hard labor.
THE ORIGIN OF HIV
• HIV genome and life cycle were similar to Simian
Immunodeficiency Viruses (SIV’s)
o Family of viruses that infect a variety of primates.
• Logical Hypothesis: HIV derived from one of SICs
o SIV moved from its primates’ host into human
o Test: Beatrice Hahn and colleagues sequenced
genes from several SIVs and compared to variety
of HIV strains.
• HIV-1 was transmitted to humans from chimpanzees
happened more than 70 years ago.
• HIV-2 was originated from monkeys, most likely in sooty
mangabeys hunted for food or kept as pets
• HIV-2 circulates primarily in West Africa and is less virulent
than HIV-1
• Jean-Christophe Plantier and colleagues gives more detail in
the history of HIV-1
o Strains of HIV-1 appear on distinct branches
arising within chimp SIVs
o Evidence shows that SIV jumped from great apes
to human at least three times.
o HIV-1 Group M is responsible for 95% of HIV
infections
WHEN DID SIV MOVE FROM CHIMPANZEES TO HUMANS?
• Group M is responsible for the bulk of the Global AIDS
pandemic.
• The last common ancestor of the group M HIV-1 viruses
lived in the 1930s or earlier.
o Patients who live in Kinshasa, Democratic
Republic of Congo, collected samples on 1959 and
1960.
§ Groups of M viruses but quite different
from each other.
§ 1960 strains had time to diverge
considerably from common ancestor.
§ Common ancestor has lived in either a
chimpanzee or human.
• A key difference between SIV infections in monkeys versus
SIV infection in chimps and HIV-1 infections in humans is
that when monkey SIVs infect their natural host, they
generally cause little or no overt disease.
1.5 WHY IS HIV LETHAL?
A CORRELATION BETWEEN LETHALITY AND TRANSMISSION?
• First level of natural selection
o There are differences among virions in their
ability to survive and reproduce within a given
host
• Second level of natural selection
o Viral strains differ in their ability to most from one
host to another.
• Strains that are good at getting transmitted will become
more common overtime; strains that are bad will disappear.
• Rare strain of HIV-1 exist that kill their host more slowly that
common strain.
o Seldom transmitted from one host to another
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• HIV-2 less damaging to its host than most strains of HIV-1
o Trasmitted at lower rates
• Christopher Fraser and colleagues (2007) evaluated this
hypothesis in two data set.
o First data set: collected in Amsterdam before the
development of highly effective antiretroviral
therapy
§ Involved 123 men– Male–Male sex
§ Estimate the effect of viral load during
asymptomatic phase of infection on the
time until pression to AIDS.
§ THE HIGHER THE VIRAL LOAD, THE
MORE QUICKLY PATIENTS DEVELOP
SYMPTOMS
o Second data set: collected in Zambia
§ Involved over 1000 heterosexual
couples (another partner had and the
other did not)
§ Estimate the effect of viral load on the
rate of transmission
§ THE HIGHER THE VIRAL LOAD, THE
GREATER THE RATE AT WHICH THE
INFECTED PARTNER PASSED THE VIRUS
ON.
• Calculate the estimated transmission potential (in new
infections) as a function of viral load
o Multiplied the duration of AIDS- free infection by
rate of transmission
o Suggest: there may be optimum viral load for HIV
transmission.
o The actual average viral loads are on the same
order of magnitude as the predicted optimum.
SHORTSIGHTED EVOLUTION?
• HIV populations within individual hosts evolve resistance to
AZT and other retroviral drugs.
o Evolve the ability to evade host’s immune
response.
• Antibodies and killer T cells recognize HIV and HIV- infected
cells by binding to epitopes
o Short piece of viral protein displayed on the
surface of the virion or the infected cell.
o Encoded in HIV’s genes
• After enters to chronic phase, HIV population changed.
o Variant easily targeted by first wave of immune
attach have disappeared.
• Research by A.J. Leslie and colleagues (2004) is an example
of a mutation that helps HIV virions evade the immune
response of patients
o Mutation affects an epitope in a protein called
p24 – component of the capsule that surrounds
the core of the HIV virion.
o Infected host cells display this epitope on their
surface, along with a host protein called a human
leucocyte antigen or HLA.
o When T-cells recognizes the foreign epitope along
with HLA, it destroys the infected cell.
• From more than 300 patients, most of HIV strains have
threonine as the third amino acid in the epitope
• However, patients who carries two allele HLA-B-B5801 or
B57 has the third amino of Asparagine.
Evolutionary Analysis Chapter 1
• The patient cell reacted strongly to the version of threonine
rather than asparagine
• The evolution of HIV population appears to contribute to
death of host in three ways:
1. Continues evolution toward novel epitopes enable the
viral population to stay far enough ahead of immune
response to avoid elimination.
2. The viral population within many hosts evolves towards
ever more aggressive replication.
The competitive fitness of the patient’s virions steadily increased over
time. The longer a patient harbors an HIV population, the more
damaging the virions in the population become.
3. Strains of HIV evolve can infect naïve T cells.
• HIV ability to infect a cell type is determined by its
coreceptor
o In early infections, virions use CCR5 as their
coreceptor.
§ Found in macrophages and on
regulatory, resting and effector T cells.
o As infection progress and HIV population evolves,
virions exploit different coreceptor
§ Strain of X4 viruses use protein called
CXCR4 and CXCR4 which found on naïve
T cells.
• The average T cell counts in the patient without X4 viral held
fairly steady over time; the average counts of patients with
X4 strains fell.
• When virions arise that undermine the immune system’s
ability to replenish its stock of T cells, they apparently
accelerate the immune system’s demise.
• Evolution of HIV within a host is shortsighted
o Virions do not look to the future and anticipate
that as their evolution evolves, it will ultimately
kill the host.
A SURPRISING CLUE
• Philippe Lemey and colleagues (2007)
o Analyzed the set collected by Raj Shankarappa
and colleagues in the lab of James Mullins (1999)
o Shankarappa collected HIV samples from nine
patients and first tested positive but 6 to 12 years
later, seven had developed AIDS.
• Lemey tally the rate of evolution for non-synonymous and
synonymous mutation
o Non-synonymous mutations alter the sequence
of amino acids in the encoded protein and subject
to natural selection
o Synonymous mutation do not alter the sequence
of amino acid and likely to be neutral.
• The speed at which patient progressed to AIDS would be
connected to the rate at which non-synonymous mutation
accumulated.
• Lemey found a relationship between progression of AIDS
and the rate at which synonymous mutation accumulated
o New variants arise by mutation and disappear
again shortly.
• Patients whose immune system activate most aggressively
against HIV develop AIDS more quickly.
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o Experience higher rate of viral replications which
mean more mutation mean a higher rate of
neutral evolution.
• Despite high rates of viral replication, natural host of SIV
avoid chronic immune activation and also avoid AIDS.
UNUSUAL FEATURES OF HIV OR HUMANS?
• Comparison of HIV versus SIVs
o HIV has extra gene called vpu which arise in the
common ancestor of a group closely related to SIV
that infect monkey Cercopithecus.
o vpu was picked up by ancestor of chimpanzee SIV
when two different strain of SIV infected the
same animal
o vpu block the action of of host protein called
tetherin
§ ties maturing virions to the membrane
of host cell, preventing their release.
• In SIV, vpu does not interfere with tetherin, but they have
nef which plays the role.
• Human tetherin is resistant to nef
o Due to loss of five amino acids from the protein
• HIV-1 group M has evolved a version of vpu that blocks
tetherin which is the reason why group M has spread
rapidly.
• TRIM5α – host cell protein which are unusual features of
human as host
o Blocks retroviral replication
o Interact with the contents of the invading virion
after they have entered the cell and before
reverse transcription of viral genome begins.
o Human TRIM5α cannot block HIVs replication
• Sara Sawyer and colleagues (2005)
o TRIM5α featured high rate of diversification
among species in amino acid of protein.
o Changes have been concentration in SPRY domain
§ Suspected to have contact with TRIM5α
o Swapping the rhesus monkey version of SPRY
patch into human TRIM5α gene gave the encoded
protein the ability to block HIV replication.
§ Diminish its potency against the virus
• Melvyn Yap and colleagues (2005) found out the
substitution of glutamine for arginine at position 332
substantially improved human TRIM5α ability to stop HIV.
• Kaiser and colleagues
o Extinct virus PtERV1 are known for many copies of
its genome, disabled by mutation, that persist in
the chromosomes of the chimpanzee and gorillas.
o They infer the sequence of PtERV1 gag gene which
encodes the viral protein disrupted by TRIM5α
o Modification a mouse retrovirus by replacing the
gag gene with PtERV1
o Test the virus’s ability to infect target cells that
make no TRIM5α, normal human TRIM5α and
human TRIM5α with glutamine at position 332.
§ Human TRIM5α does which confer more
resistance to PtERV1 than does human TRIM5α
with glutamine at position 332
§ Human TRIM5α with glutamine at position 332
confers more resistance than the normal human
protein.
Evolutionary Analysis Chapter 1
SUMMARY
The story of HIV demonstrates that evolutionary analysis
has practical applications outside of textbooks and class-
rooms. HIV/AIDS has killed some 30 million people, most of
them Africans.
Each time an HIV virion invades a host cell, the virion
reverse-transcribes its RNA genome into a DNA copy that
serves as the template for the next generation of virus
particles. Because reverse transcription is error prone, an
HIV population quickly develops substantial genetic
diversity. Some genetic variants replicate rapidly while
others die. As a result, the composition of the population
changes over time. That is, the population evolves.
HIV populations within patients quickly evolve resistance to
any single antiretroviral drug and can even evolve
resistance to multidrug cocktails. Without effective
antiretroviral therapy, HIV populations also continuously
evolve to evade the host’s immune response, a process that
ultimately contributes to the collapse of the immune
system and the onset of AIDS.
Just as HIV populations evolve in response to selection
imposed by their hosts, so too host populations may evolve
in response to selection imposed by the virus. Human
populations harbor genetic variation for susceptibility to
HIV infection. If, during the AIDS epidemic, susceptible
individuals die at higher rates than resistant individuals,
then genetic composition of these populations will change
BRIAN PAGUIA 2MBIO7
over time. The search for genetic variation for resistance to
HIV has led to the development of new antiretroviral drugs.
HIV belongs to a family of viruses that infect a va- riety of
primates. Evolutionary trees based on genetic comparisons
reveal that HIV-1 jumped to humans from chimpanzees and
has done so more than once. HIV-1 also may have jumped
to humans from gorillas. The strains responsible for the bulk
of the HIV/AIDS pandemic, HIV-1 group M, have a common
ancestor that lived several decades ago.
Comparison of HIV to evolutionarily related viruses, and of
humans to related hosts, has provided insight into why HIV
infection is lethal. HIV-1 possesses a gene not present in
most SIVs. This gene may have made it advantageous for
another of HIV’s genes to lose its ability to suppress immune
activation in the host. Immune activation, in turn, plays a
crucial role in progression to AIDS. Humans may be
particularly susceptible to HIV due to a genetic change that
evolved in our ancestors because it conferred resistance to
another retrovirus that is now extinct.
By focusing in this chapter on adaptation and di-
versification in HIV, we introduced topics that will resonate
throughout the text: mutation and variation, competition,
natural selection, evolutionary tree re- construction,
lineage diversification, and applications of evolutionary
theory to scientific and human problems.