Download Natural History of HIV/AIDS

Natural History of HIV/AIDS
Acquired immune deficiency syndrome
(AIDS) caused by Human
Immunodeficiency Virus (HIV).
Disease first described in 1981.
Immune system attacked. Victim dies of
secondary infections.
Scale of problem
The WHO estimated that in 2009 about 33.4
million people (including about 2.1 million
children) were infected with HIV.
In 2008 an estimated two million people died of
HIV infection (about 76% in sub-Saharan Africa)
and an estimated 2.7 million new infections
occurred.
Globally, infection rates are highest in subSaharan Africa, but also are high in southeast Asia.
HIV Transmission
HIV transmitted in bodily fluids –semen, blood, vaginal fluid, breast
milk. Enters via mucous membranes or into blood stream.
About 5-10% of new infections result from male-male sexual
intercourse and about two thirds of all infections from male female
intercourse.
Transmission by needle sharing accounts for about 10% of infections
and about 5-10% of infections occur in health care settings (needle
sticks, contaminated blood products)
About 11% of infections are of babies who acquire the virus during
childbirth or from breastfeeding.
Prevalence of infection among
adults age 15-45.
Controlling HIV transmission
Some success has been achieved in
reducing transmission of the virus.
Education is the single most effective
weapon in fighting infection.
Increased latex condom use reduces
transmission.
The Human Immunodeficiency
Virus
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 co-receptor, usually
CCR5.
Host cell membrane and viral coat fuse and
virus contents enter cell.
What the virus inserts
RNA genome: codes for several proteins.
Reverse transcriptase: transcribes viral RNA
into DNA
Integrase: this enzyme splices DNA into
host DNA
Protease: this enzyme involved in
production of viral proteins
Viral DNA inserted in host DNA produces
HIV mRNA and all components of virus
Viral particles self assemble and bud from
host cell.
HIV budding from
human immune cell
HIV hard to treat
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 host’s body
How HIV causes AIDS
Human body responds to infection with
HIV by mobilizing the immune system.
The immune system 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.
How HIV causes AIDS
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 begins to divide into
memory T cells and effector T cells.
Memory T cells
Memory T cells do not engage in current
fight against 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
Effector T cells attack the virus. They produce
signaling molecules called chemokines that
stimulate B cells to produce antibodies to the
virus.
Effector T cells also stimulate macrophages to
ingest cells infected with the virus.
In addition effector T cells stimulate killer T cells
to destroy infected cells displaying viral proteins.
Why is HIV hard to treat?
Viral disguise
Killer T cells deplete helper T cells (those
that produce memory cells that can
remember and recognize HIV).
Loss of helper T cells is costly, but the
immune system now primed to recognize
and attack the viral protein.
What’s the problem?
Why is HIV hard to treat?
Viral disguise
Virus mutates and the proteins on its outer
surface (gp120 and gp41) change.
These new surface proteins are not
recognized by the immune system’s
memory cells.
Mutant virus particles bearing new surface
proteins survive immune system attack and
begin new round of infection
Why is HIV hard to treat?
Viral disguise
Each round of infection reduces numbers of helper
T cells because they are infected by virus and
destroyed.
Furthermore, because each lineage of T cells has a
limited capacity for replication, after a finite
number of rounds of replication the body’s supply
of helper T cells becomes exhausted. The immune
system eventually is overwhelmed and collapses.
Why is HIV hard to treat?
Drug resistance.
AZT (azidothymidine) was the first HIV
wonder drug
It works by interfering with HIV’s reverse
transcriptase, which is the enzyme the virus
uses to convert its RNA into DNA so it can
be inserted in the host’s genome.
Why is HIV hard to treat?
Drug resistance.
AZT is similar to thymidine (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. The
azide blocks the attachment of next
nucleotide in the DNA chain.
Why is HIV hard to treat?
Drug resistance.
AZT was successful in tests although with
serious side effects.
But patients quickly stopped responding to
treatment.
Evolution of AZT-resistant HIV in patients
usually took only about 6 months.
How does resistant virus differ?
The reverse transcriptase gene in resistant
strains differ 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.
How did resistance develop?
HIV reverse transcriptase very error prone.
About half of all DNA transcripts produced
contain an error (mutation).
HIV highest mutation rate known.
There is thus enormous VARIATION in the
HIV population in a patient.
High mutation rate makes occurrence of AZTresistant mutations almost certain.
NATURAL SELECTION now starts to act in the
presence of AZT.
Natural selection means that certain variants are
better able to survive and reproduce than others.
These variants produce more offspring and
contribute more copies of their genes to the next
generation.
Selection in action
The presence of AZT suppresses replication
of non-resistant strains.
Resistant strains are BETTER ADAPTED
to the environment.
Resistant strains reproduce more rapidly.
There is thus DIFFERENTIAL
REPRODUCTIVE SUCCESS of HIV
strains.
Selection in action
Resistant strains replicate and pass on their
resistant genes to the next generation.
Thus resistance is HERITABLE.
Selection in action
AZT-resistant strains replace non-resistant
strains. The HIV gene pool changes from
one generation to the next.
EVOLUTION has occurred: EVOLUTION
is change in the gene pool from one
generation to the next.
Evolution of HIV population in an individual patient
Process of natural selection
Variation in population – some members of a population
possess alleles [recall alleles are different versions of a gene]
that make them better adapted to the environment than others.
Variation is heritable – these beneficial alleles can be
passed on to offspring.
Variation affects reproductive success – Individuals differ
in how many offspring they produce. Those individuals who
are better adapted to the current environment [those with the
best alleles for the current environment] leave behind more
offspring and so pass more copies of their alleles on to the
next generation.
Process of natural selection
Differential reproductive success results in some
alleles becoming more common in the gene pool
and other alleles less common and eventually
extinct.
As a result of the process of natural selection, the
gene pool changes from one generation to the
next. This change in the frequency of alleles from
one generation to the next is Evolution.
Using selection bases thinking to
devise better treatment regimens.
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.
Using selection to devise better
treatment regimens.
Because HIV mutates so rapidly treatment
with a single drug will not be successful for
long.
Is there a better way?
Using selection to devise better
treatment regimens.
Most successful approach has been to use
multi-drug cocktails (referred to as HAART
[Highly Active Anti-Retroviral Treatments]
HAART cocktails usually use three
different drugs in combination (e.g. two
reverse transcriptase inhibitors and a
protease inhibitor).
Using selection to devise better
treatment regimens.
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.
Using selection to devise better
treatment regimens.
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.
Using selection to devise better
treatment regimens.
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
Using selection to devise better
treatment regimens.
Multi-drug treatments have proven very
successful in reducing viral load and
reducing mortality of patients.
Using selection to devise better
treatment regimens.
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.
Using selection to devise better
treatment regimens.
For patients on HAART whether HIV replication
is stopped completely or not is crucial. In some
HIV appears dormant and no replication means no
evolution.
In other patients replication occurs, although
slowly. However, this allows HIV to mutate and
resistance to develop. So far, few HAART
regimens are effective for more than 3 years.
Using selection to devise better
treatment regimens.
Other downside of HAART therapy is that
many patients experience severe side
effects.
These patients have difficulties maintaining
their treatment regimen.
Using selection to devise better
treatment regimens.
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?
What is likely to happen to the HIV
population in the patient?
Natural resistance to HIV
Some people appear resistant to the virus not
becoming infected even though exposed to HIV
multiple times.
HIV enters T cells using co-receptor molecules on
cell’s surface. Some resistant individuals possess a
mutant CCR5 co-receptor protein whose gene is
missing 32 base pairs. This allele is referred to as
the CCR5 Δ32 allele.
Natural resistance to HIV
Frequency of the CCR5-Δ32 allele is
highest in European populations (9%), but
scarce or absent elsewhere.
Frequency of CCR5- Δ32 allele in the Old World
Natural resistance to HIV
Suggested that the allele either became
widespread by chance (genetic drift) or
provided a selective advantage against
another disease (e.g. plague or smallpox).
Natural resistance to HIV
Other mutant alleles have also been
identified that confer resistance.
Study of how these mutant alleles hinder
HIV is useful in developing new drugs (e.g.,
one drug called Schering C binds to the
CCR5 receptor and prevents HIV using it to
enter cells.)
Origins of HIV
Where did HIV come from?
HIV similar to virus found in monkeys and apes
called SIV (simian immunodeficiency virus).
To identify ancestry of HIV scientists have
sequenced various HIV strains and compared them
to various SIV strains.
Origins of HIV
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.
Origins of HIV
HIV-1 occurs in three different subgroups
(called M,N and O) and each appears
closely related to a different chimpanzee
SIV strain.
Origins of HIV
Thus, it appears that HIV-1 jumped to
humans from chimps on at least 3
occasions.
Most likely the virus was acquired through
killing and butchering chimps and monkeys
in the “bushmeat” trade.
When did HIV move to humans?
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.
When did HIV move to humans?
Extrapolating based on rates of change of
different strains suggests that subgroup M
probably infected humans in the early
1930’s.