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Genetic impact of vaccination on breakthrough HIV-1 sequences from the STEP trial

Abstract

We analyzed HIV-1 genome sequences from 68 newly infected volunteers in the STEP HIV-1 vaccine trial. To determine whether the vaccine exerted selective T cell pressure on breakthrough viruses, we identified potential T cell epitopes in the founder sequences and compared them to epitopes in the vaccine. We found greater distances to the vaccine sequence for sequences from vaccine recipients than from placebo recipients. The most significant signature site distinguishing vaccine from placebo recipients was Gag amino acid 84, a site encompassed by several epitopes contained in the vaccine and restricted by human leukocyte antigen (HLA) alleles common in the study cohort. Moreover, the extended divergence was confined to the vaccine components of the virus (HIV-1 Gag, Pol and Nef) and not found in other HIV-1 proteins. These results represent what is to our knowledge the first evidence of selective pressure from vaccine-induced T cell responses on HIV-1 infection in humans.

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Figure 1: Maximum-likelihood phylogenetic tree of gag sequences.
Figure 2: Epitope-specific protein distances between epitopes from founder sequences and the MRKAd5 HIV-1 vaccine sequence.
Figure 3: Protein distances between epitopes from founder sequences and HXB2 or HIV-1 CON_B04.
Figure 4: Amino acid signature sites.
Figure 5: Summary of sequence analyses and IFN-γ ELISPOT data.

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Acknowledgements

We thank the study participants for their time and dedication; the HIV Vaccine Trials Network Laboratory Program, the Statistical Center for HIV/AIDS Research & Prevention and Core staff who contributed to the study implementation and analysis; the Merck functional teams: the Clinical Research Specialist Organization, Worldwide Clinical Data Management Operation, Clinical Research Operations, J.T. Herbeck and B.B. Larsen for comments on the manuscript, and the Clinical Assay and Sample Receiving Operations. This work was supported by US Public Health Service grant AI41505.

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M.R., A.C.D., P.B.G., and J.I.M. designed the sequence analysis. M.R., A.C.D., P.B.G., C.A.M., L.H., B.S.M., W.D., F.L. and J.I.M. conducted the analyses. M.R., A.C.D., N.F., P.B.G. and J.I.M. analyzed the data. M.R., A.C.D., N.F., P.B.G. and J.I.M. wrote the manuscript. J.I.M., F.E.M., S.T., E.S.-B. and N.F. designed lab experiments. M.B., A.B., A.O., J.C., T.J., M.N., K.W., H.Z., D.N.R., S.S., J.N.S. and N.F. performed lab experiments. J.H., L.C., S.B., D.R.C., M.N.R., A.D., M.J.M., S.G.S., S.D., N.L.M., J.K. and J.S. conducted the STEP trial, provided material and oversaw laboratories.

Corresponding author

Correspondence to James I Mullins.

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Competing interests

M.N.R. and D.R.C. are paid employees of Merck, own Merck stock and have Merck stock options.

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Supplementary Methods, Supplementary Results, Supplementary Tables 1 and 2 and Supplementary Figures 1–5 (PDF 1931 kb)

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Rolland, M., Tovanabutra, S., deCamp, A. et al. Genetic impact of vaccination on breakthrough HIV-1 sequences from the STEP trial. Nat Med 17, 366–371 (2011). https://doi.org/10.1038/nm.2316

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