Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.
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Origins of Human AIDS Viruses
Elizabeth Bailes
Institute of Genetics
University of Nottingham
Gibbon
Orangutan
Gorilla
Chimpanzee
Human
0.05
A G
C T
Purines
Pyrimidines
Parallel MrBayes
written by Fredrik Ronquist and John Huelsenbeck
mtDNA data of Brown et al. (1982)
Model Tree
Molecular Evolution
Example
**
Collaborators
University of Alabama at BirminghamBeatrice H. Hahn George M. ShawMario Santiago Brandon KeeleFred Bibollet-Ruche Yingying LiJun Takehisa Yalu Chen
University of Montpellier University of UlmMartine Peeters Frank KirchhoffEric Delaporte Michael SchindlerFran Van HeuverswynFlorian Liegeois
Tai Forest: Friederike Range (Vienna), Ronald Noe (Strasbourg)Cameroon: Severin Loul, Eitel Mpoudi Ngole, Yanga Bienvenue
University of Nottingham Paul M. Sharp (University of Edinburgh)Elizabeth BailesLouise WainJohn Brookfield
In 2005 an estimated 39 million people were living with HIV
Origins of AIDS viruses?
(Human Immunodeficiency Viruses)
HIV-1• Group M - global (subtypes A-K) • Group N - very rare• Group O - rare
HIV-2 • Group A - epidemic in W.Africa • Group B - epidemic in W.Africa • Groups C-H - unique cases
Env protein divergence:
HIV-1 v. HIV-2: 60%
HIV-1 M v. O: 50%
HIV-1 M subtypes: 30%
gagvpr env
vifrev rev
tatpol
SIVgsnLTR LTR
neftat vpu
HIV-1 and HIV-2 retrovirusesRNA genome (2 copies)reversed transcribed into DNA
HIV-1 genome
AIDS viruses
HIV-1
Visna
MMTV
SRV-1
HERV-K
RSV
HTLV-I
HTLV-II
BLV
MLV
FLV
WDSV
FFV
SFV
Lentivirus
Spumavirus
Gamma
Delta
Alpha
Beta
Epsilon
Retroviridae
Lentiviruses
SIV: Simian Immunodeficiency Virus
- SIVcpz …. chimpanzee
- SIVagm … African green monkey species: vervet, grivet, tantalus, sabaeus
- SIVsyk …. Sykes’s monkey
- SIVsmm … sooty mangabey
- SIVlho .… L’Hoest’s monkey
- SIVsun … sun-tailed monkey
- SIVmnd … mandrill
- SIVcol .… colobus monkey
- SIVmac, SIVstm … macaques
25 0 my
MacaqueYellow baboonChacma baboonColobusLangur
MandrillDrillSooty mangabey
HumanChimpanzeeBonoboGorillaOrangutanGibbonSykes'sVervetGrivetTantalusSabeausPatasL'Hoest'sSun-tailedPreussi's
Agile mangabey
Primates infected with lentiviruses
> 30 species of African primates naturally infected with SIV
SIV infections: natural acquired not known
Natural infections:• >50% of adults• nonpathogenic
Chimpanzee the only ape
Features of SIV/HIV evolution
• Cross-species transmission• Fast rate of evolution• Recombination
• monkey to monkey
• monkey to ape
• ape to ape
Features of SIV/HIV evolution
• Cross-species transmission• Fast rate of evolution• Recombination
Reverse transcriptase mutation rate : 3.4 x 10-5 /site/replicationViral replication rate: ~ 1 day per ‘generation’
Evolution rate: ~ 5 x 10-3 substitutions/site/yr
Features of SIV/HIV evolution
• Cross-species transmission• Fast rate of evolution• Recombination
Reverse transcriptase mutation rate : 3.4 x 10-5 /site/replicationViral replication rate: ~ 1 day per ‘generation’
Evolution rate: ~ 5 x 10-3 substitutions/site/yr
HIV-1: - high diversity within a patient
- rapid evolution of drug resistance
- globally: > 30% difference in Env proteins
Features of SIV/HIV evolution
• Cross-species transmission• Fast rate of evolution• Recombination
gag pol env
recombination
A B C
gag
BA C
pol
A B C
env
A B C
Features of SIV/HIV evolution
• Cross-species transmission• Fast rate of evolution• Recombination
gag pol env
recombination
A B C
gag
BA C
pol
A B C
env
A B CImplies dual infection
Results in discordant phylogenies
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Gag Pol1 Pol2 Env
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SIVgsn
SIVmusSIVmon
SIVsyk
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*SIVdeb
* SIVden*
SIVgriSIVtan
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HIV-2SIVsm
SIVgsn
SIVsyk
SIVdeb
*
* SIVmnd2SIVdrl*
* SIVsab
*SIVrcmSIVrcm
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SIVcpzSIVcpz
SIVsunSIVlho
SIVmnd1SIVcol
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SIVgsnSIVgsnSIVmusSIVmonSIVmon
SIVsykSIVsyk
SIVdebSIVdeb
HIV-2SIVden
SIVsm*
*
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**
*
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SIVrcmSIVrcm
SIVmnd2SIVdrl
SIVcpzSIVcpz
SIVsabSIVgri
SIVtanSIVsun
SIVlhoSIVmnd1
SIVcol
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SIVgsnSIVgsn
SIVmusSIVmonSIVmon
HIV-2SIVsm
SIVsunSIVlho
SIVmnd1SIVgriSIVtanSIVrcmSIVrcmSIVmnd2SIVdrl
SIVcpzSIVcpz
SIVsabSIVdeb
SIVdeb
SIVsykSIVsyk
SIVdenSIVcol
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* *
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* *
**
* **
*
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SIVgsnSIVgsn
SIVmus
SIVmonSIVmon
SIVcpzSIVcpz
SIVdebSIVdebSIVden
SIVsykSIVsyk
SIVgriSIVsabSIVtanSIVrcmSIVrcm
HIV-2SIVsm
SIVmnd2SIVdrl
SIVsunSIVlho
SIVmnd1SIVcol
Primate lentiviruses - SIVs
Numerous differences in branching order
Origin of HIV-2
HIV-2SIVsm
SIVrcmSIVrcm
SIVmnd2SIVdrl
HIV-2SIVsm
SIVcpzSIVcpz
SIVsabSIVgri
SIVtanSIVsun
SIVlhoSIVmnd1
SIVcol
Gag Pol1 Pol2 Env
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* *
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*SIVdebSIVdeb
SIVden
SIVsykSIVsyk
SIVgsnSIVgsnSIVmus
SIVmonSIVmon
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*
*
* *
*
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*
**
*
*
*
*
*
SIVsunSIVlho
SIVmnd1SIVrcmSIVrcmSIVmnd2SIVdrl
SIVcpzSIVcpz
SIVsabSIVgriSIVtanSIVgsnSIVgsn
SIVmusSIVmonSIVmon
SIVcolSIVdebSIVdeb
SIVdenSIVsykSIVsyk
*
*
**
*
*
*
HIV-2SIVsmSIVrcmSIVrcm
SIVsunSIVlho
SIVmnd1SIVcol
SIVcpzSIVcpz
SIVsab
* * SIVmnd2SIVdrl
*
* SIVgriSIVtan
*
*
*
*
*
*
SIVgsnSIVgsnSIVmusSIVmon
SIVsykSIVsyk
SIVdebSIVdeb
SIVden
*
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**
* *
**
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*
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***
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HIV-2SIVsm
SIVrcmSIVrcmSIVgriSIVsabSIVtan
SIVmnd2SIVdrl
SIVsunSIVlho
SIVmnd1SIVcol
SIVgsnSIVgsnSIVmonSIVmon
SIVmusSIVcpz
SIVcpz
SIVsykSIVsyk
SIVdebSIVdebSIVden
sooty mangabey (Cercocebus atys)
HIV-2 geographic origin: West Africa• coastal forest Senegal to Cote D’Ivoire
• numerous Liberia, Sierra Leone, Cote D’Ivoire
• kept as pets
• Tai forest, Cote D’Ivoire
96FR12034 HIV-2 H
SIVsmmTaï31
99
99100
100
100
100
98
100
100
100
100
99
SIVsmmTaï37SIVsmmTaï1SIVsmmTaï23
CAM2 60415K
SIVsmmCI2SIVsmmCI8
SIVsmmTaï29SIVsmmTaï32
Abt96 HIV-2 GSIVsmmTaï13
SIVsmmTaï22SIVsmmTaï33
SIVsmmTaï17SIVsmmTaï3
SIVsmmTaï35SIVsmmF098
2238 HIV-2 CEHO
UC1SIVsmmSL93-063
SIVsmmSL93-119SIVsmmSL92B
SIVsmmSL92C
gp41
HIV-2 A
HIV-2 B
Multiple origins of HIV-2
Eight groups of HIV-2 - each due to a separate cross-species transmission
= 8 transmissions
HIV-2 groups interspersed among SIVsmm
96FR12034 HIV-2 H
SIVsmmTaï31
99
99100
100
100
100
98
100
100
100
100
99
SIVsmmTaï37SIVsmmTaï1SIVsmmTaï23
CAM2 60415K
SIVsmmCI2SIVsmmCI8
SIVsmmTaï29SIVsmmTaï32
Abt96 HIV-2 GSIVsmmTaï13
SIVsmmTaï22SIVsmmTaï33
SIVsmmTaï17SIVsmmTaï3
SIVsmmTaï35SIVsmmF098
2238 HIV-2 CEHO
UC1SIVsmmSL93-063
SIVsmmSL93-119SIVsmmSL92B
SIVsmmSL92C
gp41
HIV-2 A
HIV-2 B
Multiple origins of HIV-2
Two epidemic groups of HIV-2 (A and B) - most closely related to SIVsmm from Cote d’Ivoire (Tai Forest)
Phylogeographic clustering SIVsmm – Tai Forest and Sierra Leone
Primate LentivirusesHIV-1
Did HIV-1 come from chimpanzees?
First SIVcpz (Gab1) described in 1990
Second SIVcpz (Ant) described in 1996
But: So:- chimpanzees are not monkeys - maybe chimps not the
reservoir- SIV in chimpanzees seemed very rare- acquired from some monkey species?- Gab1 and Ant strains as divergent as SIVs in different AGM species
Origin of SIVcpzGag Pol1 Pol2 Env
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SIVsmSIVrcm
SIVrcm
SIVgriSIVtan
SIVgsnSIVgsnSIVmus
SIVmon
SIVsykSIVsyk
SIVdebSIVdeb
SIVden
SIVcpzSIVcpz
*
SIVsmSIVrcmSIVrcm
SIVgriSIVtan
SIVcpzSIVcpz
SIVgsnSIVgsnSIVmusSIVmonSIVmon
SIVsykSIVsyk
SIVdebSIVdeb
SIVden
SIVsmSIVrcmSIVrcm
SIVgriSIVtan
SIVcpzSIVcpz
SIVgsnSIVgsn
SIVmusSIVmonSIVmon
SIVdebSIVdeb
SIVsykSIVsyk
SIVsykSIVsyk
SIVden
SIVsmSIVrcmSIVrcm
SIVgriSIVtan
SIVgsnSIVgsnSIVmonSIVmon
SIVmusSIVcpz
SIVcpz
SIVdebSIVdebSIVden
SIVsmSIVsmSIVsmSIVsm
SIVcpz: mosaic of SIVrcm and SIVgsn/mon/mus
Hybrid origin of SIVcpz/HIV-1 genome
vpu
Hybrid origin of SIVcpz/HIV-1 genome
env-nef gap
Origins of HIVs
SIVcpz
•Hybrid of two monkey SIV genomes
•Unique genome structure identical to HIV-1
•Diversity?
P.t.verus
P.t.vellerosus
P.t.troglodytes
P.t.schweinfurthii
Chimpanzee (Pan troglodytes) subspecies
P.t.verus (and P.t.vellerosus) apparently not infected with SIVcpz
25 0 my
MacaqueYellow baboonChacma baboonColobusLangur
MandrillDrillSooty mangabey
HumanChimpanzeeBonoboGorillaOrangutanGibbonSykes'sVervetGrivetTantalusSabeausPatasL'Hoest'sSun-tailedPreussi's
Agile mangabeyX
Origin of SIVcpz in chimpanzees
SIVcpz subspecies clades
P.t.troglodytes P.t.schweinfurthii
“central chimpanzees” “eastern chimpanzees”-west central Africa - central Africa || Ancestors of HIV-1
3 origins HIV-1- interspersed SIVcpzPtt
X
X
X
Group M global distribution
Group N
very rare
Group O
rare
Non-invasive samplingFaecal samples obtained from remote locations in west central Africa,
Virus-specific antibodies
Viral RNA
Host DNAmtDNA typing (subspecies)nDNA microsatellite fingerprints
Methodology verified with captive chimps and habituated chimps in Gombe.Santiago et al. (2002) ScienceSantiago et al. (2003) J. Virology
Sampling of wild chimpanzees
7 sites negative - 1 P.t.vellerosus WE - 6 P.t.troglodytes
GT,BB,BQ,CP,DG,MG2 sites low prevalence - MT 5%, DP 4%3 sites higher prevalence - EK 29%, LB 23%, MB 35%
Phylogeographic clustering SIVcpzPol gp41
100
99
100
96
100
98
97
97
100
100
99
95
100
100
SIVcpz MB66
SIVcpzMB245SIVcpzMB248
SIVcpz LB7SIVcpzMB192
SIVcpzMB23SIVcpzMB317
HIV-1 HIV-1
HIV-1 HIV-1
SIVcpzEK519
SIVcpzEK502SIVcpzEK505
SIVcpzEK516
SIVcpz CAM3SIVcpz CAM5
SIVcpz USSIVcpz GAB2
SIVcpz GAB1SIVcpz CAM13
SIVcpzDP25SIVcpzDP206
SIVcpzMT115SIVcpzMT145
HIV-1 HIV-1
SIVcpz TAN1SIVcpzTAN2SIVcpzTAN3
SIVcpzANT
group M
group N
group O
100
100
100
100
100
96
100
100
100
100
100
100
96
100
100
100
100
SIVcpz MB66SIVcpzMB245
SIVcpz LB7SIVcpzMB192SIVcpzMB23
SIVcpzMB317SIVcpzLB186
SIVcpzEK519SIVcpzEK502
SIVcpzEK505SIVcpz GAB2
SIVcpz CAM3SIVcpz CAM5
SIVcpz USSIVcpzDP25
SIVcpzDP206SIVcpz GAB1
SIVcpz CAM13SIVcpzMT115SIVcpzMT145
SIVcpz TAN1SIVcpzTAN2
SIVcpzTAN3SIVcpzANT
HIV-1 HIV-1 HIV-1
HIV-1
group M
group N
HIV-1 HIV-1
group O
gp41- DP and EK separated by Dja river
- MB and LB not isolated
MB+LB closest relatives of HIV-1 MEK closest relatives of HIV-1 N
- also sites with highest prevalence
Diversification of HIV-1 M B RF
A U455
C ETH2220
H VI991
K EQTB11
SIVcpz/Ant
SIVcpz/Gab1
SIVcpz/Cam5
B LAID 94UG114D ELI
A 92UG037
G SE6165G 92NG083J SE9280
J SE9173
C 92BR025
H 90CF056
F1 VI850F1 93BR020
F2 MP255F2 MP257
O MVP1580
N YBF30N YBF106
SIVcpz/US
O ANT70
K MP535
M
N
O
After transmission to humans -
Subtypes:
N.America/Europe: B
Sub-Saharan Africa: all others (ACDFGHJK)
greatest diversity -
Kinshasa
Date HIV-1 M group origin B RF
A U455
C ETH2220
H VI991
K EQTB11
SIVcpz/Ant
SIVcpz/Gab1
SIVcpz/Cam5
B LAID 94UG114D ELI
A 92UG037
G SE6165G 92NG083J SE9280
J SE9173
C 92BR025
H 90CF056
F1 VI850F1 93BR020
F2 MP255F2 MP257
O MVP1580
N YBF30N YBF106
SIVcpz/US
O ANT70
K MP535
M
N
O
~1930
Dating:Sharp et al. (2000) Biochem.Soc.Trans.Korber et al. (2000) ScienceSalemi et al. (2001) FASEB J.
Origin of HIV-1 M
Kinshasa
Origin HIV-1 O group?HIV-1 M A
HIV-1 M B
SIVcpz LB7
SIVcpz MB66
HIV-1 N
HIV-1 N
SIVcpzEK505
SIVcpz CAM3
SIVcpz CAM5
SIVcpz US
SIVcpz CAM13SIVcpz GAB1
SIVcpzMT145
SIVcpz GAB2
HIV-1 O
HIV-1 O
SIVcpzANT
SIVcpz TAN1
SIVcpzTAN2
SIVcpzTAN3
SIVcpz LB7
SIVcpz MB66
HIV-1 N
HIV-1 N
HIV-1 M AHIV-1 M B
SIVcpzEK505
SIVcpz CAM3
SIVcpz CAM5
SIVcpz US
SIVcpz GAB2
SIVcpzMT145
SIVcpz CAM13
SIVcpz GAB1HIV-1 O
HIV-1 O
SIVcpzANT
SIVcpz TAN1SIVcpzTAN2
SIVcpzTAN3
X
X
?
HIV-1 M and N groups cross-species transmissions from chimpanzees
SIV in wild gorillas
Van Heuwerswyn et al., Nature, 9 November 2006
SIVcpzANT
SIVcpzTAN3
SIVcpzTAN2
SIVcpzTAN197
100
HIV-1 OHIV-1 O
SIVgorBQ664
SIVgorCP684
SIVgorCP1436100
100
100
SIVcpzMT145
SIVcpzMT115SIVcpzDP25
SIVcpzDP206
SIVcpzCAM13
SIVcpzGAB1
100
100 SIVcpzCAM5
SIVcpzUS
100
100
100
SIVcpzEK519
SIVcpzEK505
SIVcpzEK50290
HIV-1 N
HIV-1 N
100
100
100
SIVcpzGAB2
HIV-1 M BHIV-1 M A
SIVcpzLB7SIVcpzMB23
SIVcpzMB192
SIVcpzMB317
SIVcpzLB186
100
SIVcpzMB66
SIVcpzMB245100
99
95
100
100
100
100
0.05
SIVcpzCAM3
Were gorillas source of HIV-1 O group?
X chimp -> gorilla X chimp -> gorilla X gorilla -> human X chimp -> human
X XX X
SIVgor early SIVgor late
In conclusion:
• Source of AIDS viruses are African monkey viruses, SIVs, characterized by cross-species transmission and recombination
• SIVcpz genome - hybrid origin , unique genome structure
• likely source of epidemic HIV-2:
- sooty mangabeys (SIVsmm) in Côte d’Ivoire
• likely source of pandemic (group M) HIV-1:
- chimpanzees (SIVcpz) in SE Cameroon
• likely source of rare (group N) HIV-1:
- chimpanzees (SIVcpz) in S central Cameroon
• source of group O HIV-1 ?:
- gorillas ? chimpanzees ?
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