The evolution of HIV Why is HIV fatal?. Lethal strains are favored, due to “Short sighted” evolution within hosts Transmission rate advantages.

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

• Epitopes are fragments of molecules

• They elicit immune responses

• The epitopes below are a fragment of the HIV capsid protein p24

Seletion for epitope diversity in HIV strains evades immune response

image from NIH

T = Thr

N = Asn

From Leslie et al. 2004

• One amino acid

change in this epitope

greatly reduces

immune response

• 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)

N favored

T favored

Fig. 1.17 Evolutionary change in HIV population within one patient (from Shankarappa et al. 1999)

Note:

• steady, rapid evolution of genetic differences

• slows down at 6-8 yrs.

(in DNA coding for the gp120 surface protein)

Virus concentration remained high, so reduced number of mutations is unlikely

Did HIV evolution slow down due to decline in mutations?

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

Low virulence, low mortality

Low transmission rate per encounter

High virulence, high mortality

High transmission rate per encounter

X

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

Strain 1

Strain 2

Strain 3

Strain 4

Strain 5

Strain 6

AC

D

B

A, B, C, and D are

“ancestral” strains.

New mutations caused

these to “split” into two

or more descendant

strains.

Parts of HIV phylogenetic trees

Strain 1

Strain 2

Strain 3

Strain 4

Strain 5

Strain 6

AC

D

B

Branches connect descendants to ancestors. Branches represent lineages, and represent time periods of independent evolution.

More ancient

More recent

Time

Present day

Strain 1

Strain 2

Strain 3

Strain 4

Strain 5

Strain 6

AC

“sister strains,” each other’s closest relativeD

B

“Reading” HIV phylogenetic trees

Closely related

strains descend

from an

ancestral strain

that was

transmitted to

each of their

hosts

Strain 1 Chimpanzee

Strain 2 Chimpanzee

Strain 3 Chimpanzee

Strain 4 Human

Strain 5 Human

Strain 6 Human

AC

D

B

A, B and C must have infected chimps. D most likely is an ancestral strain transmitted from chimps to humans

Inferring transmission events

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 cross-species 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