Abstract

Live attenuated simian immunodeficiency virus (SIV) vaccines (LAVs) remain the most efficacious of all vaccines in nonhuman primate models of HIV and AIDS, yet the basis of their robust protection remains poorly understood. Here we show that the degree of LAV-mediated protection against intravenous wild-type SIVmac239 challenge strongly correlates with the magnitude and function of SIV-specific, effector-differentiated T cells in the lymph node but not with the responses of such T cells in the blood or with other cellular, humoral and innate immune parameters. We found that maintenance of protective T cell responses is associated with persistent LAV replication in the lymph node, which occurs almost exclusively in follicular helper T cells. Thus, effective LAVs maintain lymphoid tissue-based, effector-differentiated, SIV-specific T cells that intercept and suppress early wild-type SIV amplification and, if present in sufficient frequencies, can completely control and perhaps clear infection, an observation that provides a rationale for the development of safe, persistent vectors that can elicit and maintain such responses.

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Acknowledgements

This work was supported by the Bill and Melinda Gates Foundation (grant #41185), the International AIDS Vaccine Initiative (IAVI), the National Institute of Allergy and Infectious Diseases (including the US National Institutes of Health (NIH) grant R37 AI054292 (L.J.P.), contract HHSN272200900037C and the Center for HIV-AIDS Vaccine Immunology (CHAVI) program), the NIH Office of Research Infrastructure Programs (P51 OD 011092) and the National Cancer Institute (contract HHSN261200800001E). The authors acknowledge R. Desrosiers (Harvard University) for providing SIVmac239Δnef and SIVmac239Δ3; P. Johnson and T. Lui (University of Pennsylvania) for SIVsmE543Δnef; C. Miller (University of California, Davis) for SHIV89.6 and wild-type SIVmac239; D. Evans (Harvard University) for a single-cycle SIVmac239; N. Letvin for TRIM5 allele typing; and R. Wiseman and D. Watkins for MHC typing. We thank N. Winstone, A. Leon, J. Clock, A. Nogueron, L. Pan, M. Cartwright, A. Filali and P. Wilkinson for technical assistance and J. McElrath, S. Self, W. Koff, A. Okoye, J. Schmitz and J. Ahler for helpful discussion and advice.

Author information

Author notes

    • Yoshinori Fukazawa
    •  & Haesun Park

    These authors contributed equally to this work.

Affiliations

  1. Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, USA.

    • Yoshinori Fukazawa
    • , Haesun Park
    • , Richard Lum
    • , Noel Coombes
    • , Eisa Mahyari
    • , Shoko I Hagen
    • , Jin Young Bae
    • , Marcelo Delos Reyes III
    • , Tonya Swanson
    • , Alfred W Legasse
    • , Andrew Sylwester
    • , Scott G Hansen
    • , Michael K Axthelm
    •  & Louis J Picker
  2. Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, USA.

    • Yoshinori Fukazawa
    • , Haesun Park
    • , Richard Lum
    • , Noel Coombes
    • , Eisa Mahyari
    • , Shoko I Hagen
    • , Jin Young Bae
    • , Marcelo Delos Reyes III
    • , Tonya Swanson
    • , Alfred W Legasse
    • , Andrew Sylwester
    • , Scott G Hansen
    • , Michael K Axthelm
    •  & Louis J Picker
  3. Vaccine and Gene Therapy Institute-Florida, Port St. Lucie, Florida, USA.

    • Mark J Cameron
    • , Francois Lefebvre
    • , Andrew T Smith
    • , Petra Stafova
    •  & Rafick P Sékaly
  4. AIDS and Cancer Virus Program, SAIC Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.

    • Rebecca Shoemaker
    • , Yuan Li
    • , Kelli Oswald
    • , Michael Piatak Jr
    •  & Jeffrey D Lifson
  5. Vaccine Research Institute, US National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.

    • Adrian McDermott
  6. Duke University Medical Center, Durham, North Carolina, USA.

    • Guido Ferrari
    •  & David C Montefiori
  7. Statistical Center for HIV/AIDS Research and Prevention, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

    • Paul T Edlefsen

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Contributions

Y.F., R.L., N.C., E.M., S.I.H. and S.G.H. performed experiments and analyzed data, assisted by M.D.R. and J.Y.B. H.P. managed the project and analyzed data, assisted by A.S. T.S., A.W.L. and M.K.A. managed the animal protocols. M.P. and J.D.L. provided SIV and LAV quantifications, assisted by R.S., Y.L. and K.O. D.C.M. and G.F. provided neutralizing antibodies and cytotoxic antibody quantification, respectively. M.J.C., F.L., A.T.S., P.S. and R.P.S. carried out the microarray analysis and interpreted the results. P.T.E. performed the statistical analysis. L.J.P. conceived of the study, supervised experiments, analyzed data and wrote the paper, assisted by Y.F., H.P., P.T.E., A.M., R.P.S. and J.D.L.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Louis J Picker.

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DOI

https://doi.org/10.1038/nm.2934

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