Transcript HIV Evolution

The Evolution of HIV
Biology and natural history of the
virus
Fig. 1.1 Global incidence of HIV/AIDS. Number of
cases and per cent of adults infected, ages 15-45. Data
from UNAIDS (2005).
1/5th in
South and
SE Asia
3/5th’s of
HIV+ cases
in Africa
Three global epidemics
Recent epidemic in Russia and Ukraine
The epidemic in Africa
From UNAIDS (2006)
Botswana
Zimbabwe
Swaziland
Lesotho
In sub-Saharan
Africa
Life expectancy at birth in
Botswana
Fig. 1.5 The life cycle of HIV
Extracellular stage:
transmission
Intracellular
stage: replication
• CD4 protein is found
on T cells, HIV “uses”
CD4 to invade them
• CD4 serves important
functions in the
immune system
• e.g. CD4 aids in binding
of macrophages to
helper T (TH) cells
– stabilizes antigen
“presentation” to TH cell
– TH cells play a central
role in both pathways of
immunity
HIV: a
retrovirus—DNA
is reversetranscribed from
viral RNA by
reverse
transcriptase
Intracellular
replication stages
How does HIV cause AIDS?
TEM of HIV budding (arrow) from a T lymphocyte
(image: R. Hunt, Univ. S. Carolina)
• Simple answer: depletion of T cells killed by
HIV replicating within them suppresses
immunity, leading to opportunistic infections
• Complete answer:
– complex: immune activation hastens collapse by
providing host cells
– close phylogenetic relative, SIV, provides useful
model for studying this
Fig. 1.8a Viral load in an untreated patient
• rapid increase, followed by drop, steady
recovery (reflects immune response)
• evolution within patient of declining target cell
selectivity
Fig. 1.8b T cell depletion
• decline, recovery, collapse of T cell population
• drastic decline in gut (vulnerable to pathogen
attack)
• slow disease onset
Fig. 1.8c Activation of the immune system
• remains highly activated throughout!
• enhances rate of destruction of HIV infected
cells, but
• provides steady source of host T cells
• exhausts limited capacity to re-supply killed T cells
The evolution of HIV
Why do AZT and other antiviral
drugs fail over the long term?
Fig. 1.9 How AZT blocks DNA synthesis by HIV reverse
transcriptase
RT mistakes azidothymidine (AZT) for
the normal
nucleoside (T)
Fig. 1.9 How AZT blocks DNA synthesis by the reverse
transcriptase of HIV
the azide group
on AZT stops
DNA synthesis
and RT falls off
AZT treatments
• Initially, low doses dropped viral
load, increased CD4 T cell counts
• Increasing doses, over time, lost
effectiveness
• No evidence that patient’s enzymatic
activation of AZT declined
Evolution of AZT
resistance
• A change in the genetic composition
of patient’s viral population?
• To test
– Sample virus from patient over time as
AZT treatment progresses
– Grow virus on cells in culture
– Test inhibitory action of increasing
doses of AZT
Fig. 1.11 Evolution of AZT resistance within individual patients
from Larder et al. (1989)
HIV
populations
can take only
6 months to
evolve high
AZT
resistance
Some random
reverse
transcriptase
mutations will cause
“shape changes” in
the active site
(arrow), allowing
them to recognize
and not pick up AZT
Space-filling model of
reverse transcriptase
[from Cohen (1993)].
The large groove is
where RNA template
and nucleotides bind.
Drug resistance
mutations (in red:
includes the AZTR
mutations) are located
within this groove
Fig. 1.14 How populations
of HIV evolve AZT
resistance (through natural
selection within patients)
HIV mutation rates
• High replication rate: 10 million to 100 million
new virions per day (Ho et al. 1995, Wei et al.
1995)
• High reverse transcriptase mutation rate (~1
mutation/genome/ replication)
– polymerase is error prone
– HIV lacks DNA repair