1. MHRP  The views expressed are those of the authors and should not be construed to represent the positions of the U.S. Army or the Department of Defense. Rasmi Thomas US Military HIV Research Program Walter Reed Army Institute of Research 07/21/15 Influence of Host Genetics on HIV-1 acquisition and Vaccine Efficacy

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

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

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

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

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

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

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

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

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

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

12. MHRP 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. MHRP 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. MHRP Acknowledgements MHRP, WRAIR Heather Prentice Phil Ehrenberg Karen Baldwin Nelson Michael Jerome Kim Charla Andrews Merlin Robb Mark Milazzo Gustavo Kijak Morgane Rolland 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 Duke University Georgia Tomaras David Montefiori Guido Ferrari Bart Haynes NYU, NY Susan Zolla-Pazner NIAID Bob Bailer Rick Koup

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

16. MHRP IgG-DPB1*13 effect is present across different viral subtypes Antigen (HIV-1 subtype)DPB1*13 AssociationAntigen-DPB1*13 Interaction βPDPB1*13ORP IgG (CRF01_AE)0.380.006Present0.070.003 Absent0.930.71 Interaction0.009 IgG (B)0.450.001Present0.260.005 Absent1.030.9 Interaction0.01 IgG (A)0.55<0.001Present0.310.02 Absent1.140.55 Interaction0.02 IgG (C)0.420.002Present0.190.001 Absent0.980.93 Interaction 0.006 Georgia Tomaras

17. MHRP Frequency of IgG responses to Env peptide 119-133 confers protection in DPB1*13 individuals DPB1*13 Positive Peptide (Start-End)Peptide Sequence VI, Yes Percent VI, No Percent VU, Yes Percent VU, No PercentORFisher's P 116-130LKPCVKLTPLCVTLN18.281.87.692.42.710.26 119-133CVKLTPLCVTLNCTD9.190.942.457.60.140.04 163-177TEIRDKKQKVYALFY63.636.463.636.41.00 166-180RDKKQKVYSLFYRLD27.372.742.457.60.51 169-183KKQVYALFYKLDVVP9.190.916.783.30.501.00