Influence of Host Genetics on HIV-1 acquisition and Vaccine Efficacy

1. Influence of Host Genetics on HIV-1 acquisition and Vaccine Efficacy Rasmi Thomas US Military HIV Research Program Walter Reed Army Institute of Research 07/21/15

2. The RV144 HIV-1 vaccine showed efficacy Case VE=31.2% P=0.04 Vaccine infected N=51 Placebo infected N=74 Rerks-Ngarm et al., NEJM 2009

3. HIV-1 specific antibodies correlated with risk of acquisition Case Control Vaccine Uninfected N=205 Vaccine infected N=41 IgG binding to HIV-1 Env correlated with decreased risk of acquisition Haynes et al., NEJM 2012

4. High IgG responses to gp70 antigen (aa 120-204) correlated with decreased risk of acquisition

5. Study design for testing the effect of HLA class II on acquisition and efficacy Case Control HLA class II & IgG on acquisition Vaccine Uninfected Vaccine infected Vaccine Efficacy Placebo infected Prentice et al. Sci Trans Med 2015

6. HLA-DPB1*13 is associated with increased levels of IgG

7. High IgG levels are a correlate of decreased risk of HIV-1 acquisition only in the presence of HLA-DPB1*13

8. Vaccine efficacy increases significantly in the presence of higher levels of IgG and DPB1*13

9. IgG responses to certain Env peptides are DPB1*13 restricted

10. Magnitude of IgG responses to Env peptide 119-133 confers protection in DPB1*13 individuals DPB1*13

11. HLA-DPB1*13 exerts immune pressure on the virus

12. IgG and HLA class II findings • Presence of HLA-DPB1*13 correlates with higher quantities of IgG antibody levels and associates with decreased risk of HIV-1 acquisition and increased vaccine efficacy. • Frequency and magnitude of IgG responses to Env peptide 119-133 confers protection in DPB1*13 individuals • Vaccine-induced responses are exerting pressure on the virus in DPB1*13 individuals.

13. Conclusions • HLA class II genes modulate the quantity of antibody responses and efficacy observed in the RV144 study. • Differences in vaccine-induced responses elicited by individuals with HLA-DPB1*13 allele need to be examined closely. • Understanding how variation in the host relates to the vaccine-induced responses clarifies interpretation of vaccine efficacy studies and could prospectively improve HIV vaccine design.

14. Acknowledgements MHRP, WRAIR Heather Prentice Phil Ehrenberg Karen Baldwin Nelson Michael Jerome Kim Charla Andrews Merlin Robb Mark Milazzo Gustavo Kijak Morgane Rolland Duke University Georgia Tomaras David Montefiori Guido Ferrari Bart Haynes NYU, NY Susan Zolla-Pazner NIAID Bob Bailer Rick Koup RV144 Team Supachai Rerks-Ngarm Jaranit Kaewkungwal Punnee Pitisuttithum AFRIMS, Thailand Rob O’Connell Sorachai Nitayaphan FHCRC, Seattle Dan Geraghty Peter Gilbert Youyi Fong Allan DeCamp Julie McElrath NCI Richard Apps

15. IgG antibodies binding to this region of Env can block interaction with CD4 Env 121 Env residues 124 - 127 CD4 gp120 17b mAb Kwong et al. Science 1998

16. IgG-DPB1*13 effect is present across different viral subtypes Georgia Tomaras

17. Frequency of IgG responses to Env peptide 119-133 confers protection in DPB1*13 individuals