Week 1:

Lecture 1:
A case for evolutionary thinking: Understanding HIV 1

Events are increasing: exponential

HIV cases in United States
Change refers to the human population
Using viruses to describe evolution
Why? What? Where?
Are human populations evolving as a result of HIV pandemic?
Why are untreated HIV infection usually fatal?

HUMAN IMMUNODEFICIENCY VIRUS AS A CASE STUDY

One of the prime reasons to study HIV is that it continually evolves drug
resistance.
HIV was identified when some doctors reported occurrences of AIDS in males
who practice sex with other men.
-

What: Natural history for the HIV

HIV: Human Immunodeficiency Virus exhibits geographically distributed

infection patterns (ch 6 & 8) is an immunity compromising parasite, which
causes Acquired Immune Deficiency Syndrome, (AIDS) = EXEMPLIFIES
ADAPTATION AND DIVERSITY (ch 3 and 10)
-

Is a parasite: lives inside us and uses our resources

Percentage of infected people by

colour coding and number by the
circles (area of it)
Bars gives percentage of infected
people who are women, men and
children

Graphs:
S shape in India and kind of in SA
Shows relationship between region
and number of people infected
with HIV
a) Decrease in life expectancy
due to AIDS epidemic
Plot is only for SA
b) Negative trend
(mathematical) = positive
human trend (vice versa)
PLOT for worldwide pop. Red
line shows best estimate
and the gray area shows the
range of estimates

a) Cambodia: due to heterosexual sex while in Russia due to drug use

MODE IS DEPENDENT ON THE REGION

Circumcision and breast feeding are also mode of transmission. Transmission:

from an infection person directly onto a mucous membrane or into the
bloodstream of an uninfected person. Other modes of transmission:
heterosexual or homosexual sex, oral sex, needle sharing, transfusion with
contaminated blood products, other unsafe medical procedures, childbirth
and breastfeeding.
a) In sub- Saharan Africa and parts of south and southeast Asia: the primary
mode of HIV transmission is heterosexual sex; while in Russia and
Indonesia, the primary mode of transmission is injection drug use.
b) In Canada and UK, health agencies note that people who contracted HIV
from heteroxsexual sex likely did so in Sub-Saharan Africa.
Preventative measures: anti-viral drugs and condoms
-

Taking antiviral drugs reduces the transmission from an infected mother to

child by 40%
Using vaginal gels have benefits for women
Circumcision reduces the risk of contracting HIV by half in men
Using condoms at all times, reduces the risk of contracting HIV by 80%
Doing campaigns encourage people to practice safe sex worked but a study
conducted in United States with 4000 showed the method to be ineffective.
o They had their experimental group (homo men) attend one on one
counselling sessions as well.

92: drugs came in

This data is males having sex with
one another in USA
Step like pattern
Interesting pattern after 92
This data suggests that although it
has decreased, a positive trend in
contraction of new infection has
been steadily increasing. Anti-viral
drugs came in 92, it shows that
although it makes the disease
manageable for some, it has
prompted an increase in risky
sexual behavior.

HIV is an
intracellular
parasite incapable
of reproducing on
its own. HIV
invades specific
types of cells
(helper T- cells)
and harms the host
in return.

2 phases of HIV:

INFECTION FROM A CELLULAR Prespective

ii.

Extracellular phase
or infection
phase
Intracellular phase:

1) HIV particle itself (virion): two proteins gp120 (surface protein) and gp41
(anchor protein for gp120). Has two copies of RNA. Has enzymes: integrase
and protease, reverse transcriptase
2) Virion encounters a host cell: attaches to CD4 of the helper T- cell using gp41
and binds to CD4 (host surface protein) and then a Coreceptor
3) Fusion and dumps in RNA and enzyme in the cytoplasm of the host cell
4) DNA synthesis: uses reverse transcriptase to synthesize HIV DNA from the
HIVs RNA template
5) DNA splicing: of host genome (gray) and integrase is used to insert the HIV
DNA into the host genome
6) Transcription: uses host cell machinery
7) Translation: uses host cells ribosomes
8) Virion is assembled at the host cell membrane
9) New virion Buds off: takes some of the host membrane with it. Protease
cleaves immature to produce a mature protein.
10)
Mature virus to infect another cell
Pay attention to the two surface proteins

The reason HIV is difficult to treat because it uses hosts machinery at every
step as it is hard to find drugs that will intercept the virus production
pathway without having side effects on the hosts enzymatic function
effective drugs treat

HIV VIRIONS
-

Bind to two proteins that reside on host cell surfaces, CD4 and coreceptor
o CCR5 considered in chapters 6 & 8 are retroviruses (i.e. they use
reverse transcriptase to create HIV DNA and integrase to spice it
into the host genome)

RESPONSE BY IMMUNE SYSTEM

Response of the host in reponse to
the virus:
a) Dendritic Cell presents a part
of itself to the Nave T cell
these nave cells then
produce effector helper T
cells
b) These effector T cells present
the same thing to the B cells,
which matures them into
plasma cells these plasma
cells make antibodies that
bind to virus (and can
inactivate them)
Another way: effector T cells help
killer T cells release chemokines
which attack and destroy the host
cells which are infected with virus

These effector T cells do not live

long however, the ones that do,
become memory helper T cells.

T- cells are affected by the virus:

as virus exploits the CD4 and
CCR5 (coreceptor) on T cells
leading to new infections

WHAT HAPPENS WHEN A PERSON IS AFFECTED WITH HIV

When you have less than 200 cells, you are diagnosed with AIDS. You dont die of
infection as much as you suffer because you immune system has been so
thoroughly compromised. Thus, your immune system cant even survive a
simple yeast infection.
AIDS:
Occurs when the immune system fails (i.e. too few CD4 helper T cells are
available)
-

Is characterized by opportunistic infection by bacterial or fungal pathogens

that usually are innocuous in healthy individuals

WHAT HAPPENDS DURING

INFECTION (physiological level)
-

Immune system kicking into

actions makes things worse:
because Immune system
activation leads to effector
T-cell proliferation HIV
infects T-cells creates
more HIV targets makes it
worse

Why: single drug therapies ultimately fail

-

AZIDOTHYMIDINE (AZT): may be added (rather than the deoxyribonucleoside

thymidine) to a lengthening DNA strand by reverse transcriptase is less likely
to be incorporated into DNA transcripts that are produced by some variant
genomes, as their reverse transcriptase genes contains errors (i.e.,
mutations) that affect AZT reverse transcriptase interactions.
o Interferes with the reverse transcriptase but makes a lot of mistakes
accumulation of errors overtime makes the drug less effective.
Initially the therapies were very successful, but crashed and burned after.
Why? HIV population evolved. Think of patient as evolving population of cells
THOUGHT PROCESS THAT
WENT INTO THE MAKING OF
THE DRUG: AZT is very similar
to bases, only difference is that
it has an extra amine group.
Amine group blocks the
process.

Overtime population started

showing resistance to AZT. Why?
(think evolutionary)
Patient 1: 2 months, 11 montths
(same dosage only 50% effective)
therefore, have to take more
AZT to see the same effects, as
the virus population is evolving
overtime. (AZT resistance on the Y
- axis
Patient 2: same pattern
Data from 36 patients.
Typical time period for
AZT is 6 months, as
after 6 months, the
medicine is not as
effective. Why?
Because AZT makes
errors which
accumulate over time

AZT in the same patient overtime. Initially,

AZT blocks transcription. However, over
time virus evolves and reverse
transcriptase no longer adds AZT.

Or the virus recognizes AZT from bases

and does not add it any longer, or rejects it
after recognizing it

3 D model of reverse transcriptase (white)

Green (synthesized strand)
Blue (template)
Red where the molecule changes other
changes might be occurring at other places
as well but we see the red red mutation
has survived.

HIV in its replication makes mistakes (in transcribing) therefore, the protein
changes over time
Beige colour: resisitant to AZT
grey: partially resistant to AZT
Last one: highly resistant administer AZT change the environment (people)
Natural selection and its effects are environment dependent this means that one
of the ways they could have administered the drug would have been by giving the
organge pop, a little and then not administering AZT further. After a while the
original pop. Would have come back
-

Mistakes made source of evolution natural selection operates

on the variation created by mutations selecting for those which
are better suited ( in this case virus that has the ability to
overcome AZT)

LECTURE 2:

A case for evolutionary thinking: Understanding HIV2

Quickthink: Dicholoro Diphenyl Trichloroethane, DDT, was used as a
pesticide in the mid 1900s but ultimately became ineffective; using only
the HIV AZT example as a basis, one could infer that DDT became
inffective because:
a)
b)
c)
d)
e)

DDT diminished over time

Mutations yielded resistant individuals
DDT was modified to be less potent
Insect populations changed over time
Individual insect physiologies changed

Why: single drug therapies ultimately fail (Contd)

A type of therapy: HAART: highly
active antiretroviral therapy:
involves three or more drugs.
These drugs may each target
different enzymes
-

Data from Denmark

Grey: control

Prolong AIDS patient lives by

understanding the evolution.

Data from prescription:

Ppl from 0-20 to 60 -80: probably
stopped taking drugs due to side
effects
80-90: havent taken all the way:
produce 7 times

Where & When: HIV originates

4 conditions:
1) Variation: e..g variation in resistance in virus
to AZT heritable trait
2) Environment changes due to competition
3) Changes in phenotype that makes them a
better fit

Natural selection hereditable

traits
This individual has an HIV virus
that is evolving: goal is slow its
progression and evolution.

Three patients
Patient 1: earliest patient. Original
strain disappearing perhaps
resistant to AZT
Patient 1 infects patient 2 and the
bright Yellow from 2 infects
b) shows history of transmission.
Point of the diagram is that even if
we may lose some data, we still can
derive to make inferences to map its
history. We may not know when the
branching occur. Just by sampling

HIV origins:
-

Phenogram
diagrams (moved
based on
theone organism to
HIV 1 (talked about until
now) transfected
from
sequential
similarity
another) from chimpanzees
to humans
multiple times
HIV -2 transfected from monkeys
(less
deadly)
- Similarity in the reverse
HIV evolves rapidly (perhaps too rapidly for effective vaccination) multiple
transcriptase gene in a variety
drug therapy as proven somewhat effective
of different organisms
- Interpret as an evolutionary
tree
- Which is why we think that HIV
1 comes from chimps and HIV
2 came from monkeys
from cell surface protein data: we
can also deduce that HIV 1
infected chimps, then gorilla and

In these researchers have identified the common ancestor (middle in part a), part b:
common pattern and part c date it to 0 and it would be where the transmission
started
DATING HIV ORIGINS:
-

Was accomplished using an unrooted phenogram, genetic differences, and

linear regression (i.e. a molecular clock assumption every tick = that
many variations)

Revealed that the common ancestor for M group virions lived between 1915
and 1941.

Whether: human populations are evolving

-

Highest to susceptibility in Saharan africa and lowest in the norther Europe

(look at lecture 1)

This 32 allele gives resistant. After analyzing the data, what we found is
completely opp. To what we previously saw, as this allele was highly
prevalent in N. Europe while not as commonly found in Saharan Africa. Thus,
found that this allele highly frequent in less HIV populations and present less
in population with higher susceptibility to HIV
There is cost to having this allele: as having this allele makes a population
more susceptible to wseno virus (or something), thus while it may be
beneficial for HIV prominient regions, it is not very helpful in regions with that
wseno virus infection. This is called fitness tradeoff in evolution
One of the hypothesis: natural selection
2nd hypothesis (ch 6): genetic drift

Data collected from sex workers

contracting HIV: monitored their
susceptibility to HIV

Why: infections are fatal

-

The evolution of the HIV population within a host is short sighted (pg 27, P-2)
a) Asymptotic phase, as a
virus is more virulent,
takes shorter time to lead
to AIDS
b) Only 1 couple has AIDS:
general negative trend for
duration and general
positive trend for
transmission
c) A*b = c: middle value is
optimal for transmission
d) Tradeoff between
virulence and
transmission. The reason
we looked at this is that if
it is parasitic, then it may
not be beneficial as it dies
off; however, if its more
virulent, it does not