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Author Notes:

Email Address:Cynthia A. Derdeyn : cderdey@emory.edu

Author contributions: R.R.A. and C.A.D. designed research; S.L.B., K.M.K., S.A.S., and S.R. performed research.

H.L.R. and R.R.A. contributed new reagents/analytic tools.

S.L.B., K.M.K., S.A.S., S.R., E.H., H.L.R., G.S., R.R.A., and C.A.D. analyzed data; and S.L.B., K.M.K., S.A.S., E.H., H.L.R., G.S., R.R.A., and C.A.D. wrote the paper.

We gratefully acknowledge Dr. Brandon Keele for providing SGA sequences from the SIVsmE660 VH2000 challenge stock

Samuel R. DeVictor, Geovonni P. Bell, Lena A. Sheorey, Andrew D. Chang, and Mariam Dvalishvili for technical assistance

Drs. George Shaw and Katharine Bar for providing the SIVsmE660 reference Env plasmids E660.11 and E660.300-16 and their sequences

Subjects:

Research Funding:

National Institute of Allergy and Infectious Diseases/National Institutes of Health for Grants R01-AI58706 (to C.A.D.), U19-AI096187 (to E.H. and R.R.A.), and P51-RR000165 and P51-OD011132 (to the Yerkes National Primate Research Center).

Keywords:

  • SIV
  • neutralization
  • vaccine

Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses.

Tools:

Journal Title:

Proceedings of the National Academy of Sciences

Volume:

Volume 112, Number 34

Publisher:

, Pages 10780-10785

Type of Work:

Article | Final Publisher PDF

Abstract:

Although the correlates of immunological protection from human immunodeficiency virus or simian immunodeficiency virus infection remain incompletely understood, it is generally believed that medium to high titers of serum neutralizing antibodies (nAbs) against the challenge virus will prevent infection. This paradigm is based on a series of studies in which passive transfer of HIV-specific nAbs protected rhesus macaques (RMs) from subsequent mucosal challenge with a chimeric human/simian immunodeficiency virus. However, it is unknown whether nAb titers define protection in the setting of active immunization. Here we determined serum nAb titers against breakthrough transmitted/founder (T/F) SIVsmE660-derived envelope glycoprotein (Env) variants from 14 RMs immunized with SIVmac239-based DNA-prime/modified vaccinia virus Ankara-boost vaccine regimens that included GM-CSF or CD40L adjuvants and conferred significant but incomplete protection against repeated low-dose intrarectal challenge. A single Env variant established infection in all RMs except one, with no identifiable genetic signature associated with vaccination breakthrough compared with T/F Envs from four unvaccinated monkeys. Breakthrough T/F Env pseudoviruses were potently neutralized in vitro by heterologous pooled serum from chronically SIVsmE660-infected monkeys at IC50 titers exceeding 1:1,000,000. Remarkably, the T/F Env pseudoviruses from 13 of 14 monkeys were also susceptible to neutralization by autologous prechallenge serum at in vitro IC50 titers ranging from 1:742-1:10,832. These titers were similar to those observed in vaccinated RMs that remained uninfected. These data suggest that the relationship between serum nAb titers and protection from mucosal SIV challenge in the setting of active immunization is more complex than previously recognized, warranting further studies into the balance between immune activation, target cell availability, and protective antibody responses.

Copyright information:

© 2015 National Academy of Sciences

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