Origins of Human AIDS Viruses

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

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

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 Peeters Frank Kirchhoff Eric Delaporte Michael 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. AIDS viruses HIV-1 and HIV-2 retroviruses RNA genome (2 copies) reversed transcribed into DNA HIV-1 genome

7. Retroviridae

8. Lentiviruses

9. 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

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 HIV-1: - high diversity within a patient - rapid evolution of drug resistance - globally: > 30% difference in Env proteins 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

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

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

16. Primate lentiviruses - SIVs Numerous differences in branching order

17. Origin of HIV-2

18. 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 sooty mangabey (Cercocebus atys)

19. Multiple origins of HIV-2 HIV-2 groups interspersed among SIVsmm Eight groups of HIV-2 - each due to a separate cross-species transmission = 8 transmissions

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

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. Origin of SIVcpz in chimpanzees Chimpanzee (Pan troglodytes)subspecies P.t.verus (and P.t.vellerosus) apparently not infected with SIVcpz P.t.verus P.t.vellerosus P.t.troglodytes P.t.schweinfurthii X

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

29. X X X 3 origins HIV-1- interspersed SIVcpzPtt 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 • - DP and EKseparated by Dja river • MB and LB not isolated gp41 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 • B LAI • D 94UG114 • D ELI • A 92UG037 • A U455 After transmission to humans - Subtypes: N.America/Europe:B Sub-Saharan Africa: all others (ACDFGHJK) greatest diversity - Kinshasa • G SE6165 • G 92NG083 • J SE9280 • J SE9173 • M • C ETH2220 • C 92BR025 • H VI991 • H 90CF056 • K MP535 • K EQTB11 • F1 VI850 • F1 93BR020 • F2 MP255 • F2 MP257 • SIVcpz/US • SIVcpz/Cam5 • N • N YBF30 • N YBF106 • SIVcpz/Gab1 • O • O ANT70 • O MVP1580 • SIVcpz/Ant

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

35. Kinshasa Origin of HIV-1 M

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

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

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

39. In conclusion: • Source of AIDS viruses are African monkey viruses, SIVs, characterized by cross-species transmission and recombination • SIVcpzgenome - 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 ?