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 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 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: (2000) Science 287:

Strain 1 Strain 2 Strain 3 Strain 4 Strain 5 Strain 6 A C 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 A C 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 A C “sister strains,” each other’s closest relative D 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 A C 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