Dr Penny Moore

1. CAPRISA CENTRE FOR THE AIDS PROGRAMME OF RESEARCH IN SOUTH AFRICA CAPRISA is a UNAIDS Collaborating Centre for HIV Prevention Research Characterization of acute infection in South Africa and its relevance to HIV vaccine discovery - focus on neutralizing antibodies Dr Penny Moore AIDS Virus Research Unit, National Institute for Communicable Diseases, Johannesburg, South Africa

2. CAPRISA CENTRE FOR THE AIDS PROGRAMME OF RESEARCH IN SOUTH AFRICA CAPRISA is a UNAIDS Collaborating Centre for HIV Prevention Research Salim Abdool Karim, PI Koleka Mlisana Thumbi Ndung’u Carolyn Williamson Joanne Passmore Lynn Morris Clive Gray Winston Hide Registration Number: 2002/024027/08 http://www.caprisa.org

3. Introduction – neutralizing antibodies • Neutralizing antibody (nAb) responses develop in most HIV-1 infected individuals within a few months of infection (Moog et al, 1997; Richman et al, 2003; Wei et al, 2004) • Much of the variation that occurs in Env during early infection may be due to nAb pressure (Frost, 2005) • Neutralization escape extensively documented in HIV-1 subtype B and SIV – substitutions, indels, glycan shifts (Richman et al, 2003; Wei et al, 2004) • Autologous nAb response in subtype C develop to higher titres and show greater type-specificity (Li et al, 2006; Gray et al, 2007)

4. CAPRISA Development of the autologous neutralizing antibody response in early subtype C infection Median initial autologous response is 19 weeks post-infection Gray ES, Moore PL et al., JV 2007

5. CAPRISA The Early Neutralizing Antibody Response at 1 Year is Highly Type-specific Gray ES, Moore PL et al., JV 2007

6. CAPRISA The Major Target of the Early Autologous Neutralizing Antibody Response is the C3-V4 Region of the HIV-1 Subtype C Envelope Numbers and kinetics of autologous nAbs in early infection is not known Moore PL, Gray ES et al., JV 2008

7. Peak 1 Peak 2 Neutralization escape in HIV-1 subtype C – CAP88 1 month p.i. 6 months p.i. 12 months p.i. SGA derived clones from 1 month, 6 months and 12 months p.i. were tested against plasma spanning 2 years p.i. to assess neutralization escape. Moore et al., PLoS Pathogens, in press

8. Temporal variations in neutralization titers correspond to waves of evolving specificities – CAP88 Anti-C3 Anti-V1V2 • Use of heterologous chimeric envelopes suggest: • initial anti-C3 response develops, peaking at 26 weeks p.i., then waning. • second anti-V1V2 response peaking at 81 weeks p.i. Moore et al., PLoS Pathogens, in press

9. Escape mutations in CAP88

10. Limited nAb specificities drive sequential escape mutations – CAP88 cont Escape at 6 months p.i. is mediated by 2 amino acid changes in C3 Escape at 12 months p.i. is mediated by changes in V1V2 (and C3)

11. Limited and sequential nAb specificities drive sequential escape mutations – CAP177 Escape at 6 months p.i. is mediated by changes in C3 Escape at 12 months p.i. is mediated by changes in V1V2 In CAP88 and CAP177, nAbs first target the C3 region, then the V1V2 loop

12. The V1V2 region is a target of autologous nAbs and changes within V1V2 mediate escape – CAP210 V1V2 is the nAb target in CAP210 (heterologous chimera data) Escape at 12 months p.i. is mediated by changes in V1V2

13. A single specificity mediates neutralization of CAP45

14. Summary of autologous neutralizing antibody targets and escape mutations Moore et al., PLoS Pathogens, in press

15. Do autologous nAbs affect viral load? 7-fold 4-fold

16. The relationship between autologous nAbs and the development of cross-neutralizing breadth • A vaccine should aim to elicit cross-neutralizing antibodies • The specificities of antibodies in sera with neutralization breadth are largely unknown (Binley et al, 2008; Sather et al, 2009; Gray et al, in press ) • The mechanisms that lead to the development of breadth are not known – likely to be dependent in part on the autologous infecting envelopes (Rademeyer et al, 2007) • The contribution of autologous neutralizing antibodies to the development of breadth has not been explored

17. CAP256 80% The Neutralizing Antibody Response at 3 Years post-infection shows increased breadth See poster by Maphuti Madiga, MOPEA003 - “Development of intra- and inter-subtype cross-neutralizing antibodies in HIV-1 subtype C infection”

18. Development of the autologous neutralizing response in CAP256 Note: CAP256 was super-infected at about 13 weeks p.i. – Carolyn Williamson et al, unpublished data

19. Specificity of the autologous neutralizing response in CAP256 Use of heterologous chimeric envelopes suggest an initial (unknown) specificity, followed by an anti-V1V2 response

20. Development of the heterologous neutralizing response in CAP256

21. Development of the heterologous neutralizing response in CAP256

22. Development of the heterologous neutralizing response in CAP256 See poster by Maphuti Madiga, MOPEA003 - “Development of intra- and inter-subtype cross-neutralizing antibodies in HIV-1 subtype C infection”

23. Specificity of the heterologous neutralizing response in CAP256 mirrors the specificity of the autologous response V1V2 involved in epitope V1V2 not involved in epitope

24. Conclusions • One or two potent but highly-type specific neutralizing antibody specificities develop in the first year of infection • The C3 and V1V2 regions are frequent targets, and changes in these regions directly mediate escape • These antibody specificities arise sequentially with titers waning as escape occurs

25. Conclusions • Autologous nAbs were temporally associated with decreased viral load in CAP88, which was abrogated by escape mutations • In CAP256, antibodies mediating autologous neutralization contributed to heterologous neutralization and this involved determinants in the V1V2 region.

26. Acknowledgements CAPRISA 002 Salim Abdool Karim (PI, UKZN) Koleka Mlisana (co-chair, UKZN) Carolyn Williamson (co-chair, UCT) CAPRISA 002 study team NICD Lynn Morris Nthabeleng Ranchobe Bronwen Lambson Elin Gray Maphuti Madiga Eleanor Cave Sarah Cohen Mary Phoswa UCT Carolyn Williamson Melissa Rose-Abrahams Gama Bandawe Florette Treurnicht CAPRISA is supported by the National Institute of Allergy and infectious Disease (NIAID), National Institutes of Health (NIH) (grant# AI51794), the National Research Foundation (grant # 67385), the Columbia University-Southern African Fogarty AIDS International Training and Research Programme (AITRP) funded by the Fogarty International Center, NIH (grant # D43TW00231) and a training grant from LifeLab, a biotechnology centre of the South African Government Department of Science and Technology. Columbia University - Southern Africa Fogarty AIDS International Training and Research Program (AITRP)