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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GenBank/EMBL/DDBJ

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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.

Author information

Author notes

    • Francine E McCutchan

    Present address: Bill and Melinda Gates Foundation, Seattle, Washington, USA.

    • Morgane Rolland
    • , Sodsai Tovanabutra
    • , Allan C deCamp
    •  & Nicole Frahm

    These authors contributed equally to this work.

Affiliations

  1. Department of Microbiology, University of Washington, Seattle, Washington, USA.

    • Morgane Rolland
    • , Laura Heath
    • , Kim Wong
    • , Hong Zhao
    • , Dana N Raugi
    • , Stephanie Sorensen
    • , Julia N Stoddard
    • , Brandon S Maust
    • , Wenjie Deng
    •  & James I Mullins
  2. US Military HIV Research Program, Rockville, Maryland, USA.

    • Sodsai Tovanabutra
    • , Eric Sanders-Buell
    • , Meera Bose
    • , Andrea Bradfield
    • , Annemarie O'Sullivan
    • , Jacqueline Crossler
    • , Teresa Jones
    • , Marty Nau
    • , Nelson L Michael
    • , Jerome Kim
    •  & Francine E McCutchan
  3. Vaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

    • Allan C deCamp
    • , Nicole Frahm
    • , Peter B Gilbert
    • , Craig A Magaret
    • , John Hural
    • , Lawrence Corey
    • , Fusheng Li
    • , Steve G Self
    • , Ann Duerr
    •  & M Juliana McElrath
  4. Merck Research Laboratories, West Point, Pennsylvania, USA.

    • Sheri Dubey
    • , John Shiver
    • , Danilo R Casimiro
    •  & Michael N Robertson
  5. San Francisco Department of Health, San Francisco, California, USA.

    • Susan Buchbinder

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Contributions

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.

Competing interests

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

Corresponding author

Correspondence to James I Mullins.

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    Supplementary Methods, Supplementary Results, Supplementary Tables 1 and 2 and Supplementary Figures 1–5

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DOI

https://doi.org/10.1038/nm.2316

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