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Journal of Virology, January 2009, p. 540-551, Vol. 83, No. 2
0022-538X/09/$08.00+0     doi:10.1128/JVI.01102-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Human Immunodeficiency Virus Type 1 Env Trimer Immunization of Macaques and Impact of Priming with Viral Vector or Stabilized Core Protein{triangledown} ,{dagger}

Andreas Mörner,1 Iyadh Douagi,1 Mattias N. E. Forsell,1,2 Christopher Sundling,1 Pia Dosenovic,1 Sijy O'Dell,2 Barna Dey,2 Peter D. Kwong,2 Gerald Voss,3 Rigmor Thorstensson,1 John R. Mascola,2 Richard T. Wyatt,2 and Gunilla B. Karlsson Hedestam1*

Swedish Institute for Infectious Disease Control, 171 82 Solna, and Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden,1 Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892,2 GlaxoSmithKline Biologicals, Rixensart, Belgium3

Received 26 May 2008/ Accepted 31 October 2008

Currently there is limited information about the quality of immune responses elicited by candidate human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env)-based immunogens in primates. Here we describe a comprehensive analysis of neutralizing antibody and T-cell responses obtained in cynomolgus macaques by three selected immunization regimens. We used the previously described YU2-based gp140 protein trimers administered in an adjuvant, preceded by two distinct priming strategies: either alphavirus replicon particles expressing matched gp140 trimers or gp120 core proteins stabilized in the CD4-bound conformation. The rationale for priming with replicon particles was to evaluate the impact of the expression platform on trimer immunogenicity. The stable core proteins were chosen in an attempt to expand selectively lymphocytes recognizing common determinants between the core and trimers to broaden the immune response. The results presented here demonstrate that the platform by which Env trimers were delivered in the priming (either protein or replicon vector) had little impact on the overall immune response. In contrast, priming with stable core proteins followed by a trimer boost strikingly focused the T-cell response on the core sequences of HIV-1 Env. The specificity of the T-cell response was distinctly different from that of the responses obtained in animals immunized with trimers alone and was shown to be mediated by CD4+ T cells. However, this regimen showed limited or no improvement in the neutralizing antibody responses, suggesting that further immunogen design efforts are required to successfully focus the B-cell response on conserved neutralizing determinants of HIV-1 Env.

* Corresponding author. Mailing address: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Box 280, S-171 77 Stockholm, Sweden. Phone: 46-8-457-2568. Fax: 46-8-337272. E-mail: gunilla.karlsson.hedestam{at}ki.se

{triangledown} Published ahead of print on 12 November 2008.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, January 2009, p. 540-551, Vol. 83, No. 2
0022-538X/09/$08.00+0     doi:10.1128/JVI.01102-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Dosenovic, P., Chakrabarti, B., Soldemo, M., Douagi, I., Forsell, M. N. E., Li, Y., Phogat, A., Paulie, S., Hoxie, J., Wyatt, R. T., Karlsson Hedestam, G. B. (2009). Selective Expansion of HIV-1 Envelope Glycoprotein-Specific B Cell Subsets Recognizing Distinct Structural Elements Following Immunization. J. Immunol. 183: 3373-3382 [Abstract] [Full Text]  


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