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Polyvalent vaccines for optimal coverage of potential T-cell epitopes in global HIV-1 variants

Abstract

HIV-1/AIDS vaccines must address the extreme diversity of HIV-1. We have designed new polyvalent vaccine antigens comprised of sets of 'mosaic' proteins, assembled from fragments of natural sequences via a computational optimization method. Mosaic proteins resemble natural proteins, and a mosaic set maximizes the coverage of potential T-cell epitopes (peptides of nine amino acids) for a viral population. We found that coverage of viral diversity using mosaics was greatly increased compared to coverage by natural-sequence vaccine candidates, for both variable and conserved proteins; for conserved HIV-1 proteins, global coverage may be feasible. For example, four mosaic proteins perfectly matched 74% of 9-amino-acid potential epitopes in global Gag sequences; 87% of potential epitopes matched at least 8 of 9 positions. In contrast, a single natural Gag protein covered only 37% (9 of 9) and 67% (8 of 9). Mosaics provide diversity coverage comparable to that afforded by thousands of separate peptides, but, because the fragments of natural proteins are compressed into a small number of native-like proteins, they are tractable for vaccines.

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Figure 1: Upper bounds on epitope coverage of HIV-1 M-group Gag, Nef and Env proteins.
Figure 2: Mosaic initialization, scoring and optimization.
Figure 3: Mosaic strain coverage for all HIV proteins.
Figure 4: Coverage of M-group sequences by different vaccine candidates, nine-mer by nine-mer.
Figure 5: Overall coverage of vaccine candidates.

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References

  1. Nabel, G.J. HIV vaccine strategies. Vaccine 20, 1945–1947 (2002).

    CAS  Article  Google Scholar 

  2. Altfeld, M. et al. HIV-1 superinfection despite broad CD8+ T-cell responses containing replication of the primary virus. Nature 420, 434–439 (2002).

    CAS  Article  Google Scholar 

  3. Gaschen, B. et al. Diversity considerations in HIV-1 vaccine selection. Science 296, 2354–2360 (2002).

    CAS  Article  Google Scholar 

  4. Korber, B. et al. Evolutionary and immunological implications of contemporary HIV-1 variation. Br. Med. Bull. 58, 19–42 (2001).

    CAS  Article  Google Scholar 

  5. Williamson, C. et al. Characterization and selection of HIV-1 subtype C isolates for use in vaccine development. AIDS Res. Hum. Retroviruses 19, 133–144 (2003).

    CAS  Article  Google Scholar 

  6. Oxenius, A. et al. HIV-specific cellular immune response is inversely correlated with disease progression as defined by decline of CD4+ T cells in relation to HIV RNA load. J. Infect. Dis. 189, 1199–1208 (2004).

    CAS  Article  Google Scholar 

  7. Barouch, D.H. et al. Control of viremia and prevention of clinical AIDS in rhesus monkeys by cytokine-augmented DNA vaccination. Science 290, 486–492 (2000).

    CAS  Article  Google Scholar 

  8. Schmitz, J.E. et al. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 283, 857–860 (1999).

    CAS  Article  Google Scholar 

  9. Barouch, D.H. et al. Viral escape from dominant simian immunodeficiency virus epitope-specific cytotoxic T lymphocytes in DNA-vaccinated rhesus monkeys. J. Virol. 77, 7367–7375 (2003).

    CAS  Article  Google Scholar 

  10. Moore, J.P. & Burton, D.R. Urgently needed: a filter for the HIV-1 vaccine pipeline. Nat. Med. 10, 769–771 (2004).

    CAS  Article  Google Scholar 

  11. Gao, F. et al. Antigenicity and immunogenicity of a synthetic human immunodeficiency virus type 1 group m consensus envelope glycoprotein. J. Virol. 79, 1154–1163 (2005).

    CAS  Article  Google Scholar 

  12. Doria-Rose, N.A. et al. Human immunodeficiency virus type 1 subtype B ancestral envelope protein is functional and elicits neutralizing antibodies in rabbits similar to those elicited by a circulating subtype B envelope. J. Virol. 79, 11214–11224 (2005).

    CAS  Article  Google Scholar 

  13. Weaver, E.A. et al. Cross-subtype T cell immune responses induced by a human immunodeficiency virus type 1 group M consensus Env immunogen. J. Virol. 80, 6745–6756 (2006).

    CAS  Article  Google Scholar 

  14. Altfeld, M. et al. Enhanced detection of human immunodeficiency virus type 1-specific T-cell responses to highly variable regions by using peptides based on autologous virus sequences. J. Virol. 77, 7330–7340 (2003).

    CAS  Article  Google Scholar 

  15. Jones, N.A. et al. Determinants of human immunodeficiency virus type 1 escape from the primary CD8+ cytotoxic T lymphocyte response. J. Exp. Med. 200, 1243–1256 (2004).

    CAS  Article  Google Scholar 

  16. Allen, T.M. et al. De novo generation of escape variant-specific CD8+ T-cell responses following cytotoxic T-lymphocyte escape in chronic human immunodeficiency virus type 1 infection. J. Virol. 79, 12952–12960 (2005).

    CAS  Article  Google Scholar 

  17. Feeney, M.E. et al. HIV-1 viral escape in infancy followed by emergence of a variant-specific CTL response. J. Immunol. 174, 7524–7530 (2005).

    CAS  Article  Google Scholar 

  18. Killian, M.S. et al. Clonal breadth of the HIV-1-specific T-cell receptor repertoire in vivo as determined by subtractive analysis. AIDS 19, 887–896 (2005).

    CAS  Article  Google Scholar 

  19. Milicic, A. et al. CD8+ T cell epitope-flanking mutations disrupt proteasomal processing of HIV-1 Nef. J. Immunol. 175, 4618–4626 (2005).

    CAS  Article  Google Scholar 

  20. Ammaranond, P. et al. A new variant cytotoxic T lymphocyte escape mutation in HLA-B27-positive individuals infected with HIV type 1. AIDS Res. Hum. Retroviruses 21, 395–397 (2005).

    CAS  Article  Google Scholar 

  21. Frahm, N. et al. Consistent cytotoxic-T-lymphocyte targeting of immunodominant regions in human immunodeficiency virus across multiple ethnicities. J. Virol. 78, 2187–2200 (2004).

    CAS  Article  Google Scholar 

  22. Lichterfeld, M. et al. HIV-1 Nef is preferentially recognized by CD8 T cells in primary HIV-1 infection despite a relatively high degree of genetic diversity. AIDS 18, 1383–1392 (2004).

    CAS  Article  Google Scholar 

  23. Hel, Z. et al. Improved vaccine protection from simian AIDS by the addition of nonstructural simian immunodeficiency virus genes. J. Immunol. 176, 85–96 (2006).

    CAS  Article  Google Scholar 

  24. Blagoveshchenskaya, A.D., Thomas, L., Feliciangeli, S.F., Hung, C.H. & Thomas, G. HIV-1 Nef downregulates MHC-I by a PACS-1- and PI3K-regulated ARF6 endocytic pathway. Cell 111, 853–866 (2002).

    CAS  Article  Google Scholar 

  25. Masemola, A. et al. Hierarchical targeting of subtype C human immunodeficiency virus type 1 proteins by CD8+ T cells: correlation with viral load. J. Virol. 78, 3233–3243 (2004).

    CAS  Article  Google Scholar 

  26. Kiepiela, P. et al. Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA. Nature 432, 769–775 (2004).

    CAS  Article  Google Scholar 

  27. Kong, W.P. et al. Immunogenicity of multiple gene and clade human immunodeficiency virus type 1 DNA vaccines. J. Virol. 77, 12764–12772 (2003).

    CAS  Article  Google Scholar 

  28. Bansal, A. et al. CD8 T-cell responses in early HIV-1 infection are skewed towards high entropy peptides. AIDS 19, 241–250 (2005).

    CAS  PubMed  Google Scholar 

  29. Seaman, M.S. et al. Multiclade human immunodeficiency virus type 1 envelope immunogens elicit broad cellular and humoral immunity in rhesus monkeys. J. Virol. 79, 2956–2963 (2005).

    CAS  Article  Google Scholar 

  30. Singh, R.A., Rodgers, J.R. & Barry, M.A. The role of T cell antagonism and original antigenic sin in genetic immunization. J. Immunol. 169, 6779–6786 (2002).

    CAS  Article  Google Scholar 

  31. Hanke, T., Schneider, J., Gilbert, S.C., Hill, A.V. & McMichael, A. DNA multi-CTL epitope vaccines for HIV and Plasmodium falciparum: immunogenicity in mice. Vaccine 16, 426–435 (1998).

    CAS  Article  Google Scholar 

  32. Holland, J.H. Adaptation in Natural and Artificial Systems: an Introductory Analysis with Applications to Biology, Control, and Artificial Intelligence (MIT Press, Cambridge, Massachusetts, 1992).

    Book  Google Scholar 

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Acknowledgements

The authors thank J.H. Fischer for helpful comments on the manuscript. This work was funded through an internal directed-research grant for vaccine design at Los Alamos National Laboratory (to W.F., S.P., T.B., J.T., B.T.K., K.Y., R.F. and B.H.H.), a US National Institutes of Health (NIH) HIVRAD grant (P01 consortium (to B.H., B.H.H. and N.L.).

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Correspondence to Bette T Korber.

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A patent application has been made, covering the methods and materials presented in this paper.

Supplementary information

Supplementary Fig. 1

Full overall coverage of vaccine candidates: coverage of nine-mers in B-clade, C-clade, and M-group sequences using different input data sets for mosaic optimization, allowing different numbers of antigens, and comparing to different candidate vaccines. (PDF 2773 kb)

Supplementary Fig. 2

The distribution of nine-mers by frequency of occurrence in natural, consensus, and mosaic sequences. (PDF 546 kb)

Supplementary Fig. 3

HLA binding potential of vaccine candidates. (PDF 736 kb)

Supplementary Data (PDF 212 kb)

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Fischer, W., Perkins, S., Theiler, J. et al. Polyvalent vaccines for optimal coverage of potential T-cell epitopes in global HIV-1 variants. Nat Med 13, 100–106 (2007). https://doi.org/10.1038/nm1461

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