The RV144 trial demonstrated 31% vaccine efficacy at preventing human immunodeficiency virus (HIV)-1 infection1. Antibodies against the HIV-1 envelope variable loops 1 and 2 (Env V1 and V2) correlated inversely with infection risk2. We proposed that vaccine-induced immune responses against V1/V2 would have a selective effect against, or sieve, HIV-1 breakthrough viruses. A total of 936 HIV-1 genome sequences from 44 vaccine and 66 placebo recipients were examined. We show that vaccine-induced immune responses were associated with two signatures in V2 at amino acid positions 169 and 181. Vaccine efficacy against viruses matching the vaccine at position 169 was 48% (confidence interval 18% to 66%; P = 0.0036), whereas vaccine efficacy against viruses mismatching the vaccine at position 181 was 78% (confidence interval 35% to 93%; P = 0.0028). Residue 169 is in a cationic glycosylated region recognized by broadly neutralizing and RV144-derived antibodies. The predicted distance between the two signature sites (21 ± 7 Å) and their match/mismatch dichotomy indicate that multiple factors may be involved in the protection observed in RV144. Genetic signatures of RV144 vaccination in V2 complement the finding of an association between high V1/V2-binding antibodies and reduced risk of HIV-1 acquisition, and provide evidence that vaccine-induced V2 responses plausibly had a role in the partial protection conferred by the RV144 regimen.
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We thank B. F. Haynes and F. A. Matsen for advice and comments, and I. A. Wilson and R. L. Stanfield for assistance. This study was supported in part by an Interagency Agreement Y1-AI-2642-12 between US Army Medical Research and Material Command (USAMRMC) and the National Institutes of Allergy and Infectious Diseases. This work was also supported by a cooperative agreement (W81XWH-07-2-0067) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the US Department of Defense (DOD). Additional support was provided to P.B.G. through the NIH grant 2R37AI05465-10. The opinions herein are those of the authors and should not be construed as official or representing the views of the US Department of Defense or the Department of the Army.
The authors declare no competing financial interests.
This file contains Supplementary Figures 1–5, Supplementary Methods, Supplementary Tables 1–11 and Supplementary Note 1. (PDF 973 kb)
This Supplementary Information file contains the Code for differential VE and for the site-scanning methods. (PDF 712 kb)
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Rolland, M., Edlefsen, P., Larsen, B. et al. Increased HIV-1 vaccine efficacy against viruses with genetic signatures in Env V2. Nature 490, 417–420 (2012). https://doi.org/10.1038/nature11519
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