
Chapter 1 of Zimmer and Emlen text--The
virus and the whale: how scientists study
evolution.

Your text has a nice discussion of the
evolution of the flu virus. You need to
read it and be familiar with it.

We will discuss a different example in
class– the HIV virus to illustrate the
process of natural selection.
Acquired immune deficiency syndrome
(AIDS) caused by Human
Immunodeficiency Virus (HIV).
 Disease first described in 1981.
 Transmitted through transfer of bodily
fluids.
 Immune system attacked. Victim dies of
secondary infections.

HIV, like all viruses, is an intracellular
parasite
 Parasitizes macrophages and T-cells of
immune system
 Uses cells enzymatic machinery to copy
itself. Kills host cell in process.

HIV binds to two protein receptors on
cell’s surface : CD4 and a coreceptor,
usually CCR5.
 Virus inserts its contents into cell.

RNA genome
 Reverse transcriptase: transcribes viral
RNA into DNA
 Integrase: this enzyme splices DNA into
host DNA
 Protease: this enzyme involved in
production of viral proteins

HIV budding from
human immune cell
Because HIV hijacks the host’s own
enzymatic machinery: ribosomes,
transfer RNAs, polymerases, etc. it is hard
to treat.
 Drugs that targeted these would target
every cell in the hosts body

Immune system attacks the virus.
 It destroys virus particles floating in
bloodstream and also destroys cells
infected with virus.
 Unfortunately, the cells that HIV infects
are critical to immune system function.

HIV invades immune system cells
especially helper T cells.
 These helper T cells have a vital role in
the immune system.
 When a helper T cell is activated (by
having an antigen [a piece of foreign
protein] presented to it, it divides into
memory T cells and effector T cells.


Memory T cells do not fight the virus.

Instead they are long-lived and can
generate an immune response quickly if
the same foreign protein is encountered
again.

Effector T cells attack the virus.
›
They stimulate B cells to produce
antibodies to the virus.
› stimulate macrophages to ingest cells
infected with the virus.
› stimulate killer T cells to destroy infected
cells displaying viral proteins.
Initial infection with HIV reduces the pool
of CD4 Helper T cells.
 Loss of CD4 cells costly, but immune
system now ready to recognize viral
protein.
 Why isn’t HIV eliminated?

Virus mutates and the proteins on its
outer surface (gp120 and gp41) change.
 These surface proteins are not
recognized by the immune systems’
memory cells.
 Mutants are ignored by immune system
and continue to reproduce


Each round of infection reduces the
numbers of helper T cells.

Eventually, the supply of helper T cells is
exhausted, the immune system is
overwhelmed and collapses.

Patient then vulnerable to secondary
infections.
AZT (azidothymidine) was the first HIV
wonder drug
 It works by interfering with HIV’s reverse
transcriptase, the enzyme the virus uses
to convert its RNA into DNA.

AZT is similar to thymine (one of 4 bases
of DNA nucleotides) but it has an azide
group (N3) in place of hydroxyl group
(OH).
 An AZT molecule added to DNA strand
prevents the strand from growing.
 If DNA cannot be completed, viral
proteins cannot be made.

Cartoon illustration of reverse transcriptase enzyme in action.
AZT was successful in tests but patients
quickly stopped responding to
treatment.
 Evolution of AZT-resistant HIV in patients
usually took only about 6 months.

The reverse transcriptase gene in
resistant strains differs genetically from
non-resistant strains.
 Mutations are located in active site of
reverse transcriptase.
 These changes selectively block the
binding of AZT to DNA but allow other
nucleotides to be added.

HIV reverse transcriptase very error
prone.
 HIV has the highest mutation rate known
for any biological entity.
 There is thus enormous VARIATION in the
HIV population in a patient.

High mutation rate makes the
occurrence just by chance of AZTresistant mutations almost certain.
 NATURAL SELECTION now starts to act in
the presence of AZT


Presence of AZT suppresses replication of
non-resistant strains.

Resistant strains reproduce more rapidly.
There is thus DIFFERENTIAL REPRODUCTIVE
SUCCESS of HIV strains. Resistant strains
produce more offspring.

Resistant strains replicate and pass on
their resistant genes to the next
generation.

Thus resistance is HERITABLE.

AZT-resistant strains replace non-resistant
strains. The HIV gene pool changes from
one generation to the next.

EVOLUTION has occurred: Remember
evolution is change in the gene pool
from one generation to the next.
Evolution of HIV population in an individual patient
There must be variation in population –
individuals differ in their traits or
characteristics
 The variation must be heritable.
 The variation (the traits that organisms
possess) affects reproductive success
 As a result the beneficial variation
becomes more common in the next
generation


Several different types of drugs have
been developed to treat HIV.
› Reverse transcriptase inhibitors (e.g. AZT).
› Protease inhibitors (prevent HIV from
producing final viral proteins from precursor
proteins).
› Fusion inhibitors prevent HIV entering cells.
› Integrase inhibitors prevent HIV from inserting
HIV DNA into host’s genome.

Because HIV mutates so rapidly
treatment with a single drug will not be
successful for long.

Is there a better way?

Most successful approach has been to
use multi-drug cocktails (referred to as
HAART [Highly Active Anti-Retroviral
Treatments]
Using multi-drug cocktails sets the
evolutionary bar higher for HIV.
 To be resistant a virus particle must
possess mutations against all three drugs.
The chances of this occurring is a single
virus particle are very low.


If the same drugs were provided in
sequence to an HIV population each
time it faced a new drug it would need
only a single mutation to gain resistance,
which would then spread through the
population.

Offering drugs one at a time is
analagous to providing a stairway that
HIV must climb. Offering multiple drugs
at once requires HIV to leap from the
bottom to the top in a single bound,
which is much more difficult

Multi-drug treatments have proven very
successful in reducing viral load and
reducing mortality of patients.

However, HIV infection is not cured.
Reservoir of HIV hides in resting white
blood cells. Patients who go off HAART
therapy experience increased HIV loads.

A downside of HAART therapy is that
many patients experience severe side
effects.

These patients have difficulties
maintaining their treatment regimen.

Because of severe side effects of HAART
therapy some doctors have advocated
“drug holidays” for their patients (i.e. to
have patients stop taking drugs for a
while). From an evolutionary perspective
does this seem like a good idea or not?

Because a drug holiday allows HIV to
replicate it is likely to be a very bad idea.

Every time HIV replicates it produces
new mutants and this increases the
chance that a resistant form of HIV will
be produced.

Where did HIV come from?

HIV similar to viruses in monkeys called
SIV (simian immunodeficiency virus).

To identify ancestry of HIV scientists have
sequenced various HIV strains and
compared them to various SIV strains.

HIV-1 is most similar to an SIV found in
chimps and HIV-2 is most similar to an SIV
found in a monkey called the sooty
mangabey.

HIV-1 occurs in three different subgroups
(called M,N and O) and each appears
closely related to a different
chimpanzee SIV strain.

Thus appears that HIV-1 jumped to
humans from chimps on at least 3
occasions.

Most likely acquired through killing and
butchering chimps and monkeys in the
“bushmeat” trade.

Sequence data from several group M
strains has been used estimate when HIV
moved from chimps to humans.

Korber et al. (2000) analyzed nucleotide
sequence data for 159 samples of HIV-1
strain M. Constructed a phylogenetic tree
showing relatedness to a common ancestor
of the 159 samples.

Extrapolating based on rates of change
of different strains suggests that
subgroup M probably infected humans
in the early 1930’s.

To summarize: our understanding of
evolutionary biology has enabled us to
understand why HIV is so hard to treat,
devise treatment methods that take
evolution into account and reconstruct
the likely history of the disease.