1. A comparative study of adaptive molecular evolution in different HIV clades Marc Choisy CEPM UMR CNRS-IRD 9926 Montpellier, France

3. HIV-2 HIV-1

4. HIV-2 HIV-1 M HIV-1 N HIV-1 O

6. Adaptive evolution ?

7. Purifying selection Adaptive evolution Darwinian evolution (mutation + selection) Neutral evolution (mutation alone)

8. No selection Selection AAATGGCAT LysTrpThr dSdS LysTrpThr AATGGCATG dNdN AsnTrpThr AATGGCATC Molecular evolution d N /d S >1 d N /d S <1 d N /d S =1

9. envelop proteins env Lipid membrane gp41 gp120 Capsid gag RNA 0 10000 pol enzymes 1 HIV-2 A HIV-1 M A HIV-1 M B HIV-1 M C d N /d S 0 HIV-2 A HIV-1 M A HIV-1 M B HIV-1 M C

10. w = d N /d S

12. w = d N /d S = p 0 *w 0 + p 1 *w 1 + p 2 *w 2 + p 3 *w 3 w3w3 w2w2 w1w1 w0w0 p1p1 p2p2 p0p0 p3p3 w = d N /d S = p 0 *w 0 + p 1 *w 1 + p 2 *w 2 LRT

13. w = d N /d S = p 0 *w 0 + p 1 *w 1 + p 2 *w 2

14. Prior probabilities : p 0, p 1, and p 2 Posterior probabilities : f 0 i, f 1 i, and f 2 i w i = d N /d S i = f 0 i *w 0 + f 1 i *w 1 + f 2 i *w 2 5’ 3’ 2 95% 1

15. HIV-1 M A HIV-1 M B HIV-1 M D HIV-1 M C HIV-1 O HIV-2 A 95% 2 1 w i = f 0 i *w 0 + f 1 i *w 1 + f 2 i *w 2

16. 95% 1

17. 2 w i = f 0 i *w 0 + f 1 i *w 1 + f 2 i *w 2

18. Test 1 : H0 : no match between +vely selected sites H1 : match between +vely selected sites Positively selected sites tend to occur at the same position in different clades, except for HIV-2

19. Test 2 : H0 : random repartition of +vely selected sites with respect to epitopes H1 : no match between +vely selected sites and epitopes H2 : match between +vely selected sites and epitopes Positively selected sites do not tend to be related to epitopic sites H1 vs H0 H2 vs H0

20. Test 3 : H0 : no match between +vely selected sites and glycosylation sites H1 : match between +vely selected sites and glycosylation sites Positively selected sites tend to occur on N-glycosylation sites

21. Test 4 : H0 : +vely selected sites have the same strength H1 : +vely selected sites do not have the same strength Not that much difference between clades

22. CONCLUSIONS Positively selected sites tend to occur at the same position in different clades, except for HIV-2 Positively selected sites do not tend to be related to epitopic sites Positively selected sites tend to occur on N-glycosylation sites Similar intensity of selection across clades

23. CONCLUSIONS Positively selected sites tend to occur at the same position in different clades, except for HIV-2 Positively selected sites do not tend to be related to epitopic sites Positively selected sites tend to occur on N-glycosylation sites Similar intensity of selection across clades Moderates conclusions from Gaschen et al 2002

24. CONCLUSIONS Positively selected sites tend to occur at the same position in different clades, except for HIV-2 Positively selected sites do not tend to be related to epitopic sites Positively selected sites tend to occur on N-glycosylation sites Similar intensity of selection across clades Confirms the glycan shield model of Kwong et al. 2002

25. Glycan shield model (Kwong et al. 2002)

38. Contributors: C. H. Woelk, University of California San Diego, USA. D. L. Robertson, University of Manchester, UK. J. F. Guégan, CEPM, UMR CNRS-IRD 9926, Montpellier, France. Data: Kuiken, C., et al. (2000). HIV Sequence Compendium. Los Alamos, NM, USA: Theoretical Biology and Biophysics Group, Los Alamos National Laboratory. Korber, B., et al. (2000). HIV Molecular Immunology. Los Alamos, NM, USA: Theoretical Biology and Biophysics Group, Los Alamos National Laboratory. Programs: Yang, Z. H. (1997). PAML: a program package for the phylogenetic analysis by maximum likelihood. Computer Applications in the Biosciences 13, 555-556. Hansen, J. E., et al. (1998) NetOglyc: prediction of mucin type O-glycosylation sites based on sequence context and surface accessibility. Glycoconjugate Journal 15, 115-130. ACKNOWLEDGEMENTS

39. PAUP* ML on model of codon substitution d N /d S = w 0 p 0 + w 1 p 1 + w 2 p 2