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Paleovirology
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How did HIV-1 and HIV-2 adapt to humans?
AGM RCM Mandrill Colobus
Why are humans infected with some lentiviruses and not others?
Sooty Mangabey Chimpanzee Human
HIV-2
4X >7X
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Years from present
102 103 104 105 106 >107
Change(s) in the specificity of antiviral genes
Antiviral genes
Modern viruses Paleovirus
Ancient viral pathogens of humans and human ancestors have shaped our immunity to modern viruses
?
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nucleus
Primates encode antiviral factors that limit virus replication
nuclear import
integration
uncoating
reverse transcription assembly
budding
APOBEC3
Tetherin
SAMHD1
Viruses encode proteins to evade the antiviral factors
Vif
Vpu
Vpx
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nucleus
nuclear import
integration
uncoating
reverse transcription assembly
budding
APOBEC3
Tetherin
SAMHD1
Vif
Vpu
Vpx
Host susceptibility = sum of the interactions between host antiviral factors and viral antagonists
Leading to an evolutionary “arms race” between host genomes and viruses
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Viral-host ‘arms race’ and Species barriers
Host antiviral gene
Viral antagonist Host antiviral gene Viral antagonist
Host evasion
Viral adaptation
Host wins
Virus wins
Viral cross-species transmission
Host wins
Viral adaptation to recover the antagonism
… …
(Emerman and Malik, Plos Biol 2010)
Species 1 Species 1
= Successful jump
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REPLACEMENT (dN) SYNONYMOUS (dS)
PURIFYING SELECTION
dN
dS < 1
dN
dS > 1 POSITIVE
SELECTION
Virus-host interactions drive positive selection
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The ancient origins of HIV-1
SIVgor
SIVmus
SIVrcm
SIVcol
SIVgsn SIVsmm
SIVlho SIVagm
SIVmnd
SIVcpz
HIV-1
Old World monkeys Hominids
How long have HIV-like viruses been in primates?
What allowed the virus to jump to chimpanzees?
Why are humans so susceptible to HIV?
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Target cell
Producer cell
APOBEC3G
APOBEC3G inhibits HIV/SIV during reverse transcription
Packaging Reverse transcription
G > A hypermutations
Cytidine deaminase C > U
G G G
C U U
G A A
Inactivated viral genome
Viral RNA
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Target cell
Producer cell
APPBEC3G
Lentiviral Vif antagonizes APOBEC3G (A3G)
Packaging Reverse transcription
G G G
C C C
G G G
Viral infection
Viral Vif
Viral RNA Recruitment of Ub ligase complex
Proteasome degradation
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Using the virus-host interaction sites to identify ancient pathogens
time
Infection by pathogenic
virus
time
Primate species phylogeny
Virus-encoded Antagonist
virus-encoded antagonist
Antiviral Factor
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126FWKPDYQ132
Species-specific mutations in A3G govern sensitivity to Vif
A3G CD1 CD2
Vif binding
African Green Monkey A3G
Human A3G HIV-1 Vif
SIVagm Vif 126FWDPDYQ13 2
• Residue 128 of A3G is a critical determinant of Vif sensitivity
• Positive selection in this region of A3G driven by viral interactions
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126FWEPDYQ132
126FWKPHYQ132
126FWKPDYQ132
Ancient and ongoing co-evolution of AGMs and their lentiviruses
AGM Ancestor Vervet
Tantalus
Grivet
Sabaeus
126FWKPDYQ132
126FWKPDYQ132
126FWKPDYQ132
126FWKPDYQ132
A3G variants:
*
*
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Adaptive evolution of A3G in deep time: inferring ancient viruses
CD1 CD2 A3G
Have ‘escape‘ mutations in A3G emerged in other primate species?
Old World Monkeys
Compton and Emerman, PLOS Pathogens, 2013
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0
1
10
100 %
Infe
ctiv
ity
No Vif SIVdeb SIVagm.Ver
De Brazza’s A130D
A3G:
Vif:
126FWKPAYQ132
Mustached Wolf’s Guenon De Brazza’s
Compton and Emerman, PLOS Pathogens, 2013
• D130A allows escape from Vif • SIV Vif infecting Cercopithecus genus has counter-evolved
A mutation common to Cercopithecus genus allows evasion of Vif
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126FWKPAYQ132
126FWKPAYQ132
126FWKPAYQ132
126FWKPAYQ132
126FWKPDYQ132
A pathogenic lentivirus infected the Cercopithecus ancestor at least 5 MYA
Ancestor
126FWKPAYQ132
Cercopithecus
Allenopithecus
A3G variants:
Compton and Emerman PLOS Pathogens, 2013
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How old are the primate lentiviruses?
HIV-1
SIVcpz
SIVcpz
SIVcpz
SIVgor SIVmus SIVrcm SIVcol
SIVagm SIVgsn SIVsmm
SIVlho SIVmnd
SIVagm SIVmnd
A pathogenic lentivirus was present in some simian primates at least 5 million years ago. Probably longer.
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Sometimes exogenous retroviruses enter the germline
exogenous virus endogenous virus
where they become inherited and fixed within the species
Viral fossils also point to ancient pathogenic viruses
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baboon
New World monkeys
human
chimpanzee
gorilla
orangutan
gibbon
Myr 5 10 15 20 25 30 35 40 45 50 55 60 65 80-100
HERV-K
Germline acquisition of retroviral elements
MaLR
Most HERV families
few ~70 HERV-K
Human endogenous retroviruses are all defective.
8% of human genome
100,000 integrants of 31 families of retroviruses
Large numbers of Retroviral fossils in the human genome
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Implications of endogenous retroviruses in the human genome
• There have been many retroviral infections of human ancestors
• Retroviral lineages go extinct in their host
• Host wins!
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An endogenous lentivirus in the genome of a prosimian
Gifford, Katzourakis et al. PNAS, 2008
Grey mouse lemur
There was a distantly related lentivirus in a prosimian at least 4 million years ago
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The ancient origins of HIV-1
SIVgor
SIVmus
SIVrcm
SIVcol
SIVgsn SIVsmm
SIVlho SIVagm
SIVmnd
SIVcpz
HIV-1
Old World monkeys Hominids
At least 5 Mya Adaptation of an HIV-like virus to hominids
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SIVrcm SIVmus/mon/gsn
SIVcpz
Red-capped mangabeys Guenons
Chimpanzees
SIVcpz is a recombinant between two viruses from old world monkeys
23
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HIV-1
Restricted
Dendritic cells Monocytes Resting T-cells
VPX HIV-1
Not Restricted
Vpx antagonizes the host SAMHD1 protein
DCAF DDB1 CUL4
SAMHD1 VPX
dNTP
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The capacity to antagonize SAMHD1 was lost during the genesis of SIVcpz
25
vif
vif
vpr
vpr SIVrcm
SAMHD1
APOBEC3G
APOBEC3G
SAMHD1 SIVcpz
gag
pol
env
gag
pol env
vpx
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The deletion of Vpx from SIVcpz also altered Vif
Acquisition of 60-75bp
1 2 3 Vpx
109aa Vpr 101aa
Vif 223aa Fr
ames
1 2 3
Vpr 99aa
Vif 190aa
vif-vpr 61bp
Fram
es …PLP…
Loss of ~380bp
*
*
*
…SLQYLA
…SLQYLA
26
SIVrcm
SIVcpz
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Loss of vpx was driven by selection for changes in vif to gain APOBEC3 antagonism
0
1
10
100
1000
chimpA3G chimpA3D chimpA3F chimpA3H
SIVcpz Vif No Vif SIVrcm Vif
SIVcpz Vif PLP *
% v
irus
infe
ctiv
ity
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SIVrcm SIVmus
Red-capped mangabeys 5’LTR gag
pol
vif
vpr
vpu tat
env
nef
3’LTR rev
5’LTR gag
pol
vif vpr
vpx
tat env
nef
3’LTR
rev
Guenons
SIVcpz epidemic in chimpanzees
HIV-1 in humans SIVgor in gorillas
SIVcpz Vif was pre-equipped to degrade humA3G
SIVcpz
Recombination between distant SIVs
5’LTR gag
pol
vif
vpr
vpu tat
env
nef
3’LTR rev
Loss of Vpx Reconstruction of Vif
5’LTR gag
pol
vif
vpr
vpu tat
env
nef
3’LTR rev Adaptation of Vif to
chimpA3G and A3D
Hominoids
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The ancient origins of HIV-1
SIVgor
SIVmus
SIVrcm
SIVcol
SIVgsn SIVsmm
SIVlho SIVagm
SIVmnd
SIVcpz
HIV-1
Old World monkeys Hominids
~100 years ago
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Perez-Caballero et al. Cell, 30 October 2009
Tetherin directly tethers virions to cells
Counter-acted by HIV-1 Vpu which removes Tetherin from the cell surface
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Virus release is inhibited by Tetherin
No Tetherin + Tetherin
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1
10
100
No Vpu HIV Vpu SIVcpz Vpu SIVgor Vpu
Rela
tive
Infe
ctiv
ity (%
)
SIVcpz Vpu cannnot antagonize Tetherin
Lim ES, Malik HS and Emerman M. JV, 2010
Virus production in the presence of
Tetherin
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SIVsm LTR gag
pol
vif
env vpr
rev
vpx
HIV-1 LTR gag
pol
vif
env LTR
nef vpr
rev
tat
vpu
Most SIVs use Nef, not Vpu, to counteract Tetherin
LTR gag
pol
vif
env LTR
vpr
rev
tat
vpu SIVcpz
tat
nef
LTR
nef
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Primate phylogeny Codon alignment
Host-virus arms race
Positive selection “hot spot” Identifies the
Target binding surface
Evolution-guided identification of host-virus interaction sites
Purifying selection (dN/dS < 1) Positive selection (dN/dS > 1)
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Strong signal of positive selection
RVPMDDIWKKDGDKRC RVPMDDIWKKDGDKRC RVPMDAILKKDGDKRC RVPMGDICKKDGDKRC RGPMDDIWKKDGDKRC RVPMDGIWKKDGDKRC KMPMYDSCKEDGDKRC KMPMDDICKEDRDKCC KMPMDDICKEDGDKCC KMLMDDIWKEDGDKHC KMPMDDIWKEDGDKRC KMPMDDNLKEDGDKCC KMPMDDIWKEDGDKRC KMSMDDICKEDGGKRC PVPMDDFLKHERKERC PVPMDDFLKHERKERC LVPMDDFPKHERKERC LVPMDDFLKHESKERC LVPMDDFLKHERKERC
Hominoids Chimp Bonobo Gorilla Orangutan Gibbon Agile gibbon Old World Monkeys Cephus AGM Patas Talapoin Rhesus Francois leaf Douc Langur Kik Colobus New World Monkeys Woolly Howler Saki PygmyMarm Tamarin
9 17 43
TM Coiled-coil C. Tail GPI Tetherin Nef
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RVPME-----DGDKRC RVPMDDIWKKDGDKRC RVPMDDIWKKDGDKRC RVPMDAILKKDGDKRC RVPMGDICKKDGDKRC RGPMDDIWKKDGDKRC RVPMDGIWKKDGDKRC KMPMYDSCKEDGDKRC KMPMDDICKEDRDKCC KMPMDDICKEDGDKCC KMLMDDIWKEDGDKHC KMPMDDIWKEDGDKRC KMPMDDNLKEDGDKCC KMPMDDIWKEDGDKRC KMSMDDICKEDGGKRC PVPMDDFLKHERKERC PVPMDDFLKHERKERC LVPMDDFPKHERKERC LVPMDDFLKHESKERC LVPMDDFLKHERKERC
Hominoids Human Chimp Bonobo Gorilla Orangutan Gibbon Agile gibbon Old World Monkeys Cephus AGM Patas Talapoin Rhesus Francois leaf Douc Langur Kik Colobus New World Monkeys Woolly Howler Saki PygmyMarm Tamarin
9 17 43
LGVPLIIFTIKANSEAC LGVPLIIFTIKANSEAC LGVPLIIFTIKANSEAC LGVPLIIFTIKANSEAC LGVPLIIFTIKANSEAC LGVPLIIFTIKANSEAC LGVPLIIFTIKANSEA LGVLLIFFIIKANSEAC LGVPLIFFIIKANSEAC MGVPLIFFIIKASSEAC LGVPLIFFIIKANSEAC LGVPLIFFIIKANSEAC LGVLLTFFIIKANSEAC LGVLLIFFIIKANSEAC LGVLLIFFIIKANSEAC LGVLLIVYVKRANSEAC LGVFLIIYVKKANSEAC LGALLIVYVKRANSEAC LGVLLIFYVKRANSEAC LGVLLIIYVQRANSEAC
Vpu Nef TM Coiled-coil C. Tail GPI Tetherin
Human
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Viral Antagonist Tetherin
HIV-1 adapted to humans by evolution of Vpu towards the unique form of human Tetherin
Nef
Evolution of Vpu
Vpu Vpu
Rapid adaptive evolution
Nef Cannot work against human Tetherin
Only occurred in the pandemic HIV-1 (group M)
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The ancient origins of HIV-1
SIVgor
SIVmus
SIVrcm
SIVcol
SIVgsn SIVsmm
SIVlho SIVagm
SIVmnd
SIVcpz
HIV-1
Old World monkeys Hominids
The pandemic form of HIV- 1 acquired a final adaptation to humans
Viruses similar to HIV are ancient pathogens of primates
Adaptation of an HIV-like virus to hominids by gene deletion and d t ti
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Years from present
102 103 104 105 106 >107
SARS HIV DEN measles smallpox
Paleoviruses
HERV-K PtERV? Other ERV
Modern and ancient viral pathogens of humans and human ancestors
Episodic selections by ancient pathogenic viruses has driven the evolution of current innate immunity genes
genetic evidence
Modern viruses
Ancient infections influence modern virus susceptibility
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Fred Hutchinson Cancer Research Center