The evolution of HIV
Why is HIV fatal?
Lethal strains are favored,
due to
• “Short sighted” evolution within hosts
• Transmission rate advantages
“Short-sighted” evolution of HIV
cripples the immune system
• Through natural selection for strains that
evade immunity
• By favoring the fastest-replicating strains
• By selecting for “coreceptor switching”
“Short-sighted” evolution of
HIV cripples the immune
system
Through natural selection for
strains that evade immunity
Seletion for epitope diversity in HIV
strains evades immune response
• Epitopes are fragments
of molecules
• They elicit immune
responses
image from NIH
• The epitopes below are
a fragment of the HIV
capsid protein p24
T = Thr
N = Asn
• One amino acid
change in this epitope
greatly reduces
immune response
From Leslie et al. 2004
N favored
T favored
• Natural selection within
patients favors strains
with epitopes less
recognized by the
immune system
• Direction of evolution
changes, depending on
host genotype*
*B57 and B5801 are alleles
at HLA loci (involved in
immune repsonse)
Fig. 1.17 Evolutionary change in
HIV population within one patient
(from Shankarappa et al. 1999)
(in DNA coding for the gp120 surface protein)
Note:
• steady, rapid evolution
of genetic differences
• slows down at 6-8 yrs.
Did HIV evolution slow down
due to decline in mutations?
Virus concentration
remained high, so
reduced number of
mutations is unlikely
More likely that selection for gp120 epitope
diversity slowed due to collapse of the immune
system
Reduced variation in antibodies and T-cells no
longer selected for high epitope diversity
“Short-sighted” evolution of
HIV cripples immune system
By favoring the fastest-replicating
strains
Evolution of fast-replicating
strains in competition
• Competition within patients should
select for more rapidly-replicating
strains
• Troyer et al. (2005) sampled HIV from
several patients over months
• They grew them in competition with
control strains on lymphocytes in vitro
each colored line represents the
HIV population of a single host
“Short-sighted” evolution of
HIV cripples immune system
By favoring “coreceptor switching”
and infection of naive T cells
Infection requires
CD4 + coreceptor
Naive T cells
• Progenitors of
effector and
memory cells
Naive T cells
• Bear CXCR4
coreceptors
instead of
CCR5
Coreceptor switching
• In ~ 1/2 of all patients, HIV switches
from CCR5 to CXCR4 late in the
chronic stage
• Blaak et al. (2000) monitored T cells
in patients over 2 years, some with,
some without “X4 virions”
Coreceptor switching hastens
immune system collapse!
“Short-sighted” selection
for lethal HIV
• Natural selection by immune system
within patients favors
– HIV strains with novel epitopes
– Rapid replication of competing strains
– Switching to new coreceptors on naive
T cells
• Together, these exhaust immunity,
leading to fatal AIDS
within a patient, HIV “evolves itself out of existence”
The transmission rate
hypothesis
High virulence, high mortality
High transmission rate per encounter
X
Low virulence, low mortality
Low transmission rate per encounter
X
HIV-2 geographic range remains
restricted to West Africa
•Phylogenetic trees show sooty
mangabeys to be the source of HIV-2
•Sooty mangabey: found in coastal
forests from Senegal to Cote D’Ivoire
• Kept as pets throughout this range
•HIV-2 is less virulent, and its restricted
range may reflect poor transmission
Sooty Mangabey (Cercocebus atys)
Modifed from T. Quinn, M.D., NIAD, NIH
The evolution of HIV
Why are some people resistant to
HIV infection and disease
progression?
HIV resistance genes
• CCR5-32 alleles contain a 32 bp deletion in the
CCR5 coreceptor gene
• These alleles were recovered from patients showing
long survival times
• Patients exposed that remain HIV (-), and lymphocytes
in vitro show protective effect of CCR5-32
– lymphocytes from CCR5-32 / CCR5-32 homozygotes
cannot be infected by HIV
– infection rates for heterozygotes?
Fig. 1.1 Global incidence of HIV/AIDS. CCR5-32 is
uncommon in high-prevalence regions...why has there
been no evolutionary response?
The evolution of HIV
Where did HIV come from?
Hahn and coworkers:
phylogeny of HIV and
SIV strains, based on
DNA sequences of
reverse transcriptase
(1999) Nature 397: 436-441
(2000) Science 287: 607-614
Parts of HIV phylogenetic trees
Strain 1
A, B, C, and D are
“ancestral” strains.
Strain 2
A
C
Strain 3
New mutations caused
these to “split” into two
or more descendant
B
strains.
Strain 4
D
Strain 5
Strain 6
Strain 1
Strain 2
A
C
Branches connect
descendants to ancestors.
Branches represent
lineages, and represent
time periods of
independent evolution.
Strain 3
B
Strain 4
D
Strain 6
Time
More
ancient
Strain 5
More
recent
Present
day
“Reading” HIV phylogenetic trees
Strain 1
Closely related A
strains descend
from an
ancestral strain
that was
B
transmitted to
each of their
hosts
Strain 2
C
Strain 3
Strain 4
D
Strain 5
Strain 6
“sister strains,”
each other’s
closest relative
Inferring transmission events
Strain 1
Chimpanzee
A, B and C must
have infected
chimps. D most
likely is an
ancestral strain
transmitted from
chimps to humans
Strain 2
Chimpanzee
A
C
Strain 3
Chimpanzee
B
Strain 4 Human
D
Strain 5 Human
Strain 6 Human
HIV-1 and HIV-2 form
distinct lineages
• HIV-2 is closely related
to mangabey SIV
• HIV-1 is closely related
to chimp SIV
• Independent crossspecies transmission!
Cross-species
transmission of
HIV-1
• Expanded analysis of
surface protein DNA
sequences confirms
– Cross-species
transmission from chimps
– At least 3 times,
independently