Lecture 1: Evolution, HIV, and Drug

resistance

HIV virions emerging from human T cell.

I. Auto Immune
Deficiency Syndrome
HIV binds to CCR5protein on T-cells or
macrophages.
Production of new _CCR5 + CD4T_ kills T-cells
or macrophages.
Immune system compromised.
Patient dies of common infections unimpeded
by weakened immune system.

Virus Population in Treated HIV

patients

HIV and AIDS

HIV-AIDS
a plague of epic proportions

Rate of AIDS Infection

Fall and Rise of HIV Infections

Questions
Why are HIV infections so hard to treat?
Why is the success of single treatments
short-lived?
Why is the virus so virulent?
Why are some HIV-infected more
resistant to AIDS?
Where did the virus come from?
What is the best long-term strategy to
combat AIDS?

These questions can be answered, in par

by using evolutionary theory!

How Viruses Work

II. Central Dogma and how

retroviruses work

II. Central Dogma and how

retroviruses work

How Viruses Work

Human Immune-deficiency
Virus

HIV - a retrovirus

HIV - a retrovirus

III. How the body tries to

combat infections
Immune response
Many molecular players on the
stage

Definitions
An antigen is any substance that
causes your immune system to
produce antibodies against it.
An epitope is the specific part of the
antigen that the immune system
(antibodies, B-cells, T-cells) recognizes
B-cells:
T-cells:

Macrophage ingesting E. coli

http://s99.middlebury.edu/BI330A/projects/Howard/images/macropha

Short-lived

How the immune system

responds HIV infection
over time

IV. AZT and natural

selection
AZT - loses effectiveness in patients
over time. Strain of HIV becomes
resistant.
Other drugs - proteases, etc. the
cocktail

AIDS Treatments
AZT - loses effectiveness in patients
over time. Strain of HIV becomes
resistant.
Other drugs - proteases, etc. the
cocktail

AIDS Treatments
Vaccine - develop T-cell responses to
virion coat proteins (multiple strains)
Genetic engineering - 32 allele in CCR5
protein of T-cell co-receptor.

How AZT Works

How AZT Works

AZT resembles nucleotide building blocks of
DNA
Reverse transcriptase incorporates AZT in
developing DNA
Premature termination of DNA synthesis

But AZT eventually fails to work requires higher and higher doses

But AZT eventually fails to work requires higher and higher doses

But AZT eventually fails to work requires higher and higher doses

But AZT eventually fails to work requires higher and higher doses

After 10
months 10
times the
dose has
little impact
on virus.

Why AZT Eventually Fails

Reverse transcriptase is error-prone when it
assembles DNA and there are no correction
enzymes - mutations result.
One of the protein products of the DNA is the
reverse transcriptase itself.
Some mutant variants in reverse transcriptase fail
to bind AZT.
Mutants are favored

How can HIV reverse

transcriptase become resistant
to AZT?

HIV Reverse Transcriptase

Fig. 1.4 RNA groove

Red areas are areas of amino acid
substitutions that provide AZT resistance

Selecting
for AZTresistant
HIV

AIDS Treatments
AZT - loses effectiveness in patients
over time. Strain of HIV becomes
resistant. True of any single drug
treatment.
Combination with other drugs - protease
inhibitors, integrase inhibitors, etc. - the
cocktail.

V. Why does HIV evolve so

quickly?
Mutation rate is the number of nucleotides
substituted per generation of replication.
Humans (nuclear DNA) - 1 mutation for
every 109 generations
Flu Virus - 1 mutation for every 106
generations
HIV - 1 mutation for every 103 generations!

HIV evolves within

patients!

Viral protein evolves in response to attack from

antibodies and killer T-cells

Why does the HIV protein stop

changing?

Why does the HIV protein (and its

epitopes) stop changing?

VI. Where did

HIV come
from?

Phylogeny of
HIV

Tree based on sequence for

reverse transcriptase

How are such phylogenetic trees

determined?

Phylogeny of
HIV

Tree based on sequence for

proteins on surface of virus

Future AIDS Treatments

Genetic engineering - 32 allele in CCR5
protein of T-cell co-receptor. Naturally
occurring allele confers resistance in
some humans as virus cant enter cells.
Vaccine - develop T-cell responses to
virion coat proteins (multiple strains)

Take-Home Message
Transcription errors lead to different strains of
HIV - producing variation
Traits of different strains are passed from one
generation to another heritability
Not all strains survive. Those better able to
survive and reproduce increase in relative
number and pass on traits. - selection
HIV evolves, as do many diseases!

Multiple drug resistance is common

when using antibiotics (affects bacteria)
Examples?
MRSA (Methicilin-resistant
Staphylococcus aureus)
VRE (Vanocomycin-resistant
Enterococcus)
MDR TB (Multiple-drug resistant
Mycobacterium tuberculosis)

Multiple drug resistance is common

when using antibiotics (affects bacteria)

Possible new way to combat

antibiotic-resistant bacteria?

A previously uncultured bacterium, Eleftheria

terrae, makes teixobactin, a new antibiotic.
Credit William Fowle/Northeastern University

Understanding HIV and

AIDS
Central Dogma - How cells
work and reproduce.
Evolution Changes in allele
frequency over generational
time in a population of
organisms.