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Impact of pre-adapted HIV transmission

Nature Medicine volume 22, pages 606–613 (2016)Cite this article

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Abstract

Human leukocyte antigen class I (HLA)-restricted CD8+ T lymphocyte (CTL) responses are crucial to HIV-1 control. Although HIV can evade these responses, the longer-term impact of viral escape mutants remains unclear, as these variants can also reduce intrinsic viral fitness. To address this, we here developed a metric to determine the degree of HIV adaptation to an HLA profile. We demonstrate that transmission of viruses that are pre-adapted to the HLA molecules expressed in the recipient is associated with impaired immunogenicity, elevated viral load and accelerated CD4+ T cell decline. Furthermore, the extent of pre-adaptation among circulating viruses explains much of the variation in outcomes attributed to the expression of certain HLA alleles. Thus, viral pre-adaptation exploits 'holes' in the immune response. Accounting for these holes may be key for vaccine strategies seeking to elicit functional responses from viral variants, and to HIV cure strategies that require broad CTL responses to achieve successful eradication of HIV reservoirs.

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Figure 1: Adaptation of viral sequence to HLA-I alleles.
Figure 2: Autologous adaptation predicts faster disease progression.
Figure 3: Transmitted adaptation predicts clinical prognosis and largely explains which HLA alleles are protective.
Figure 4: Adaptation affects HLA–VL associations and heritability estimates.
Figure 5: CTL responses against pre-adapted transmitted epitopes are dysfunctional.

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Acknowledgements

We thank M. Carrington for comments on the manuscript, S. Riddler (University of Pittsburgh, Pittsburgh, Pennsylvania, USA) for access to HLA and sequence data from the ACTG trials, D. Claiborne (Emory University, Atlanta, Georgia, USA) for providing MJ4 proviruses with nonadapted and adapted epitopes, R.A. Kaslow and J. Tang (University of Alabama, Birmingham, Alabama, USA) for access to Zambian HLA data, and D. Goedhals and C. van Vuuren (University of Free State, Bloemfontein, South Africa) for curating additional clinical data from the Bloemfontein cohort. We thank Merck, the NIH National Institute of Allergy and Infectious Diseases (NIAID) and the NIAID-funded HIV Vaccine Trials Network for providing the clinical data set, viral sequences, HLA types and CTL response data from the Step Study (HVTN 502). We also thank the Step and ACTG 5142 and 5128 staff and trial participants, as well as the staff and volunteers of the HOMER, WAHCS, ZEHRP, Durban, Gaborone, Kimberley and Bloemfontain cohorts, for their contributions. This study was funded by NIAID (grants R01 AI112566 (P.A.G.), R56 AI098551 (P.A.G.), R01 AI64060 (E.H.), R37 AI51231 (E.H.), P01 AI074415 (T.M.A.), U01 AI 66454 (R.S.), RO1 AI46995 (P.J.R.G.) and R01 AI071906 (R.A. Kaslow and J. Tang)), the Canadian Institutes of Health Research (grants MOP-93536 and HOP-115700 (both to M.A.B. and Z.L.B.)) and the Wellcome Trust (grant WT104748MA (P.J.R.G.)). HLA typing and viral sequencing of the ACTG cohorts were supported by the NIH (grant U01 AI 068636 to R.H.), the National Institute of Mental Health (NIMH) and the National Institute of Dental and Craniofacial Research (NIDCR). Support for the ZEHRP cohort was also provided by the International AIDS Vaccine Initiative (S.A.) and made possible in part by the support of the American people through the US Agency for International Development (USAID). A full list of IAVI donors is available at http://www.iavi.org. This work was also supported in part by the Virology Core at the Emory Center for AIDS Research (grant P30 AI050409 (E.H.)), the Flow Cytometry Core at the University of Alabama at Birmingham Center for AIDS Research (grant P30 AI027767 (P.A.G.)), the Tennessee Center for AIDS Research (P30 AI110527 (S.M.)) and the Yerkes National Primate Research Center base (grant P51OD11132 (E.H.)) through the NIH Office of the Director. M.S. was supported in part by an Action Cycling Fellowship. T.N. was supported by the International AIDS Vaccine Initiative, the South African Department of Science and Technology and the National Research Foundation through the South Africa Research Chairs Initiative, by an International Early Career Scientist award from the Howard Hughes Medical Institute, and by the Victor Daitz Foundation. P.R.H. is supported by a CIHR/GSK Professorship in Clinical Virology. Z.L.B. is supported by a Scholar Award from the Michael Smith Foundation for Health Research.

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  1. Nico Pfeifer, Vincent Y F Tan & Anat Kreimer

    Present address: Present addresses: Department of Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, Saarbrücken, Germany (N.P.); Department of Electrical and Computer Engineering, National University of Singapore, Singapore (V.Y.F.T.); Department of Mathematics, National University of Singapore, Singapore (V.Y.F.T.); Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, Berkeley, California, USA (A.K.).,

  2. Victor Y Du and Nico Pfeifer: These authors contributed equally to this work.

Authors and Affiliations

  1. Microsoft Research, Redmond, Washington, USA

    Jonathan M Carlson, Nico Pfeifer, Vincent Y F Tan, Anat Kreimer, Charles E DeZiel, Nicolo Fusi & David Heckerman

  2. Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Victor Y Du, Anju Bansal & Paul A Goepfert

  3. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA

    Karen Power, Thumbi Ndung'u & Todd M Allen

  4. British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada

    Chanson J Brumme, Mark A Brockman, P Richard Harrigan & Zabrina L Brumme

  5. Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA

    Malinda Schaefer & Eric Hunter

  6. Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada

    Mark A Brockman & Zabrina L Brumme

  7. International AIDS Vaccine Initiative, New York, New York, USA

    Jill Gilmour & Matt A Price

  8. Imperial College of Science, Technology and Medicine, London, UK

    Jill Gilmour

  9. Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA.,

    Matt A Price

  10. Rwanda–Zambia HIV Research Group, Zambia–Emory HIV Research Project, Lusaka, Zambia

    William Kilembe, Susan Allen & Eric Hunter

  11. Gilead Sciences, Foster City, California, USA

    Richard Haubrich

  12. Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia

    Mina John & Simon Mallal

  13. Department of Clinical Immunology, Royal Perth Hospital, Perth, Western Australia, Australia

    Mina John

  14. Center for Translational Immunology and Infectious Diseases, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

    Simon Mallal

  15. Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA

    Roger Shapiro

  16. Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK

    John Frater

  17. National Institute of Health Research, Oxford Biomedical Research Centre, Oxford, UK

    John Frater

  18. Institute for Emerging Infections, Oxford Martin School, University of Oxford, Oxford, UK

    John Frater

  19. Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

    P Richard Harrigan

  20. HIV Pathogenesis Programme, the Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa

    Thumbi Ndung'u & Philip J R Goulder

  21. KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa

    Thumbi Ndung'u

  22. Max Planck Institute for Infection Biology, Berlin, Germany

    Thumbi Ndung'u

  23. Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA

    Susan Allen & Eric Hunter

  24. Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA

    Susan Allen

  25. Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA

    John Sidney

  26. Department of Paediatrics, University of Oxford, Oxford, UK

    Philip J R Goulder

Authors
  1. Jonathan M Carlson
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  2. Victor Y Du
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  3. Nico Pfeifer
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  6. Karen Power
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  8. Anat Kreimer
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  9. Charles E DeZiel
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  11. Malinda Schaefer
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  17. Mina John
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  28. Zabrina L Brumme
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  29. Eric Hunter
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  30. Paul A Goepfert
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Contributions

J.M.C. designed and implemented the statistical analyses and adaptation model and wrote the paper. N.P. designed and implemented the adaptation model, with help from V.Y.F.T., A.K., C.E.D. and D.H. N.F. and C.J.B. helped with the design and/or implementation of the statistical analyses. P.A.G. designed the functional studies on primary immune responses, which were performed by V.Y.D., A.B. and J.S. K.P. and T.M.A. provided controller sequences. M.S., S.A. and E.H. provided transmission pair and longitudinal sequence and clinical data. M.A.B., J.G., M.A.P., W.K., R.H., M.J., S.M., R.S., J.F., P.R.H., T.N., S.A., P.J.R.G., Z.L.B. and E.H. provided chronic infection data. J.M.C., E.H., P.A.G., Z.L.B. and P.J.R.G. advised the project and helped write the paper, with input from all other authors.

Corresponding authors

Correspondence to Jonathan M Carlson, Eric Hunter or Paul A Goepfert.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10, Supplementary Tables 1–4 and Supplementary Notes 1–3 (PDF 5342 kb)

Supplementary Data Set

Adaptation scores, escape associations, and functional data for all cohorts. (XLSX 1813 kb)

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Carlson, J., Du, V., Pfeifer, N. et al. Impact of pre-adapted HIV transmission. Nat Med 22, 606–613 (2016). https://doi.org/10.1038/nm.4100

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