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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.

Mar 28, 2015

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Page 1: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

Origins of Human AIDS Viruses

Elizabeth Bailes

Institute of Genetics

University of Nottingham

Page 2: 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

**

Page 3: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

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

Page 4: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

In 2005 an estimated 39 million people were living with HIV

Page 5: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

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%

Page 6: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

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

Page 7: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

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

Page 8: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

Lentiviruses

Page 9: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

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

Page 10: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

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

Page 11: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

Features of SIV/HIV evolution

• Cross-species transmission• Fast rate of evolution• Recombination

• monkey to monkey

• monkey to ape

• ape to ape

Page 12: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

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

Page 13: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

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

Page 14: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

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

Page 15: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

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

Page 16: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

*

Gag Pol1 Pol2 Env

*

SIVgsn

SIVmusSIVmon

SIVsyk

*

**

*SIVdeb

* SIVden*

SIVgriSIVtan

*

HIV-2SIVsm

SIVgsn

SIVsyk

SIVdeb

*

* SIVmnd2SIVdrl*

* SIVsab

*SIVrcmSIVrcm

*

**

SIVcpzSIVcpz

SIVsunSIVlho

SIVmnd1SIVcol

**

*

*

**

*

**

*

*

*

SIVgsnSIVgsnSIVmusSIVmonSIVmon

SIVsykSIVsyk

SIVdebSIVdeb

HIV-2SIVden

SIVsm*

*

**

**

*

**

SIVrcmSIVrcm

SIVmnd2SIVdrl

SIVcpzSIVcpz

SIVsabSIVgri

SIVtanSIVsun

SIVlhoSIVmnd1

SIVcol

**

*

*

*

**

* *

*

*

*

*

**

**

*

SIVgsnSIVgsn

SIVmusSIVmonSIVmon

HIV-2SIVsm

SIVsunSIVlho

SIVmnd1SIVgriSIVtanSIVrcmSIVrcmSIVmnd2SIVdrl

SIVcpzSIVcpz

SIVsabSIVdeb

SIVdeb

SIVsykSIVsyk

SIVdenSIVcol

*

*

* *

*

* *

**

* **

*

* *

**

*

*

**

SIVgsnSIVgsn

SIVmus

SIVmonSIVmon

SIVcpzSIVcpz

SIVdebSIVdebSIVden

SIVsykSIVsyk

SIVgriSIVsabSIVtanSIVrcmSIVrcm

HIV-2SIVsm

SIVmnd2SIVdrl

SIVsunSIVlho

SIVmnd1SIVcol

Primate lentiviruses - SIVs

Numerous differences in branching order

Page 17: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

Origin of HIV-2

HIV-2SIVsm

SIVrcmSIVrcm

SIVmnd2SIVdrl

HIV-2SIVsm

SIVcpzSIVcpz

SIVsabSIVgri

SIVtanSIVsun

SIVlhoSIVmnd1

SIVcol

Gag Pol1 Pol2 Env

*

**

* *

*

**

**

**

**

*

*

*

*

*

*SIVdebSIVdeb

SIVden

SIVsykSIVsyk

SIVgsnSIVgsnSIVmus

SIVmonSIVmon

*

*

*

*

* *

*

*

*

*

**

*

*

*

*

*

SIVsunSIVlho

SIVmnd1SIVrcmSIVrcmSIVmnd2SIVdrl

SIVcpzSIVcpz

SIVsabSIVgriSIVtanSIVgsnSIVgsn

SIVmusSIVmonSIVmon

SIVcolSIVdebSIVdeb

SIVdenSIVsykSIVsyk

*

*

**

*

*

*

HIV-2SIVsmSIVrcmSIVrcm

SIVsunSIVlho

SIVmnd1SIVcol

SIVcpzSIVcpz

SIVsab

* * SIVmnd2SIVdrl

*

* SIVgriSIVtan

*

*

*

*

*

*

SIVgsnSIVgsnSIVmusSIVmon

SIVsykSIVsyk

SIVdebSIVdeb

SIVden

*

*

**

* *

**

* *

*

* *

***

*

*

*

*

*

*

HIV-2SIVsm

SIVrcmSIVrcmSIVgriSIVsabSIVtan

SIVmnd2SIVdrl

SIVsunSIVlho

SIVmnd1SIVcol

SIVgsnSIVgsnSIVmonSIVmon

SIVmusSIVcpz

SIVcpz

SIVsykSIVsyk

SIVdebSIVdebSIVden

Page 18: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

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

Page 19: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

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

Page 20: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

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

Page 21: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

Primate LentivirusesHIV-1

Page 22: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

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

Page 23: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

Origin of SIVcpzGag Pol1 Pol2 Env

*

**

* *

*

*

*

*

*

*

**

*

**

*

*

*

*

**

*

**

*

*

*

*

*

*

*

*

*

**

*

*

*

***

*

*

* *

*

*

*

*

*

*

*

* *

*

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

Page 24: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

Hybrid origin of SIVcpz/HIV-1 genome

vpu

Page 25: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

Hybrid origin of SIVcpz/HIV-1 genome

env-nef gap

Page 26: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

Origins of HIVs

SIVcpz

•Hybrid of two monkey SIV genomes

•Unique genome structure identical to HIV-1

•Diversity?

Page 27: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

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

Page 28: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

SIVcpz subspecies clades

P.t.troglodytes P.t.schweinfurthii

“central chimpanzees” “eastern chimpanzees”-west central Africa - central Africa || Ancestors of HIV-1

Page 29: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

3 origins HIV-1- interspersed SIVcpzPtt

X

X

X

Group M global distribution

Group N

very rare

Group O

rare

Page 30: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

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

Page 31: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

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%

Page 32: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

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

Page 33: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

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

Page 34: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

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.

Page 35: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

Origin of HIV-1 M

Kinshasa

Page 36: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

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

Page 37: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

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

Page 38: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

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

Page 39: Origins of Human AIDS Viruses Elizabeth Bailes Institute of Genetics University of Nottingham.

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 ?