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

2. Parallel MrBayes written by Fredrik Ronquist and John Huelsenbeck mtDNA data of Brown et al. (1982) ModelTree Molecular Evolution Example * *

3. Collaborators University of Alabama at Birmingham Beatrice H. Hahn George M. Shaw Mario Santiago Brandon Keele Fred Bibollet-Ruche Yingying Li Jun Takehisa Yalu Chen University of Montpellier University of Ulm Martine PeetersFrank Kirchhoff Eric DelaporteMichael Schindler Fran Van Heuverswyn Florian 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 Bailes Louise Wain John Brookfield

4. In 2005 an estimated 39 million people were living with HIV

5. 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%

6. HIV-1 and HIV-2 retroviruses RNA genome (2 copies) reversed transcribed into DNA HIV-1 genome AIDS viruses

7. Retroviridae

8. Lentiviruses

9. SIV: Simian Immunodeficiency Virus - SIV cpz …. chimpanzee - SIV agm … African green monkey species: vervet, grivet, tantalus, sabaeus - SIV syk …. Sykess monkey - SIV smm … sooty mangabey - SIV lho.… LHoests monkey - SIV sun … sun-tailed monkey - SIV mnd … mandrill - SIV col.… colobus monkey - SIV mac, SIV stm … macaques

10. 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

11. Features of SIV/HIV evolution Cross-species transmission Fast rate of evolution Recombination monkey to monkey monkey to ape ape to ape

12. Features of SIV/HIV evolution Cross-species transmission Fast rate of evolution Recombination Reverse transcriptase mutation rate : 3.4 x 10 -5 /site/replication Viral replication rate: ~ 1 day per generation Evolution rate: ~ 5 x 10 -3 substitutions/site/yr

13. Features of SIV/HIV evolution Cross-species transmission Fast rate of evolution Recombination Reverse transcriptase mutation rate : 3.4 x 10 -5 /site/replication Viral 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

14. Features of SIV/HIV evolution Cross-species transmission Fast rate of evolution Recombination gag pol env recombination A B C gag BAC pol AB C env ABC

15. Features of SIV/HIV evolution Cross-species transmission Fast rate of evolution Recombination gag pol env recombination A B C gag BAC pol AB C env ABC Implies dual infection Results in discordant phylogenies

16. Primate lentiviruses - SIVs Numerous differences in branching order

17. Origin of HIV-2

18. sooty mangabey (Cercocebus atys) HIV-2 geographic origin: West Africa coastal forest Senegal to Cote DIvoire numerous Liberia, Sierra Leone, Cote DIvoire kept as pets Tai forest, Cote DIvoire

19. 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

20. Multiple origins of HIV-2 Two epidemic groups of HIV-2 (A and B) - most closely related to SIVsmm from Cote dIvoire (Tai Forest) Phylogeographic clustering SIVsmm – Tai Forest and Sierra Leone

21. Primate Lentiviruses HIV-1

22. 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

23. Origin of SIVcpz SIVcpz: mosaic of SIVrcm and SIVgsn/mon/mus

24. Hybrid origin of SIVcpz/HIV-1 genome vpu

25. Hybrid origin of SIVcpz/HIV-1 genome env-nef gap

26. Origins of HIVs SIVcpz Hybrid of two monkey SIV genomes Unique genome structure identical to HIV-1 Diversity?

27. 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 X Origin of SIVcpz in chimpanzees

28. SIVcpz subspecies clades P.t.troglodytes P.t.schweinfurthii central chimpanzees eastern chimpanzees -west central Africa - central Africa || Ancestors of HIV-1

29. 3 origins HIV-1- interspersed SIVcpzPtt X X X Group M global distribution Group N very rare Group O rare

30. Non-invasive sampling Faecal samples obtained from remote locations in west central Africa, Virus-specific antibodies Viral RNA Host DNA mtDNA typing (subspecies) nDNA microsatellite fingerprints Methodology verified with captive chimps and habituated chimps in Gombe. Santiago et al. (2002) Science Santiago et al. (2003) J. Virology

31. Sampling of wild chimpanzees 7 sites negative - 1 P.t.vellerosus WE - 6 P.t.troglodytes GT,BB,BQ,CP,DG,MG 2 sites low prevalence - MT 5%, DP 4% 3 sites higher prevalence - EK 29%, LB 23%, MB 35%

32. Phylogeographic clustering SIVcpz gp41 - DP and EK separated by Dja river - MB and LB not isolated MB+LB closest relatives of HIV-1 M EK closest relatives of HIV-1 N - also sites with highest prevalence

33. Diversification of HIV-1 M B RF A U455 C ETH2220 H VI991 K EQTB11 SIVcpz/Ant SIVcpz/Gab1 SIVcpz/Cam5 B LAI D 94UG114 D ELI A 92UG037 G SE6165 G 92NG083 J SE9280 J SE9173 C 92BR025 H 90CF056 F1 VI850 F1 93BR020 F2 MP255 F2 MP257 O MVP1580 N YBF30 N 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

34. Date HIV-1 M group origin B RF A U455 C ETH2220 H VI991 K EQTB11 SIVcpz/Ant SIVcpz/Gab1 SIVcpz/Cam5 B LAI D 94UG114 D ELI A 92UG037 G SE6165 G 92NG083 J SE9280 J SE9173 C 92BR025 H 90CF056 F1 VI850 F1 93BR020 F2 MP255 F2 MP257 O MVP1580 N YBF30 N YBF106 SIVcpz/US O ANT70 K MP535 M N O ~1930 Dating: Sharp et al. (2000) Biochem.Soc.Trans. Korber et al. (2000) Science Salemi et al. (2001) FASEB J.

35. Origin of HIV-1 M Kinshasa

36. Origin HIV-1 O group? X X ? HIV-1 M and N groups cross-species transmissions from chimpanzees

37. SIV in wild gorillas Van Heuwerswyn et al., Nature, 9 November 2006

38. Were gorillas source of HIV-1 O group? X chimp -> gorilla X chimp -> gorilla X gorilla -> human X chimp -> human X X XX SIVgor earlySIVgor late

39. 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 dIvoire 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 ?