Letter | Published:

HIV-1 superinfection despite broad CD8+ T-cell responses containing replication of the primary virus

  • An Addendum to this article was published on 22 May 2003

Abstract

Early treatment of acute HIV-1 infection followed by treatment interruptions has shown promise for enhancing immune control of infection1,2,3. A subsequent loss of control, however, allows the correlates of protective immunity to be assessed. Here we show that sudden breakthrough of plasma viraemia occurred after prolonged immune containment in an individual infected with HIV-1 at a time when 25 distinct CD8+ T-cell epitopes in the viral proteins Gag, RT, Integrase, Env, Nef, Vpr, Vif and Rev were being targeted. Sequencing of the virus in plasma and cells showed that superinfection with a second clade-B virus was coincident with the loss of immune control. This sudden increase in viraemia was associated with a decline in half of the CD8+ T-cell responses. The declining CD8+ T-cell responses were coupled with sequence changes relative to the initial virus that resulted in impaired recognition. Our data show that HIV-1 superinfection can occur in the setting of a strong and broadly directed virus-specific CD8+ T-cell response. The lack of cross-protective immunity for closely related HIV-1 strains, despite persistent recognition of multiple CD8 epitopes, has important implications for public health and vaccine development.

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References

  1. 1

    Lisziewicz, J. et al. Control of HIV despite the discontinuation of antiretroviral therapy. N. Engl. J. Med. 340, 1683–1684 (1999)

  2. 2

    Ortiz, G. M. et al. HIV-1-specific immune responses in subjects who temporarily contain virus replication after discontinuation of highly active antiretroviral therapy. J. Clin. Invest. 104, R13–R18 (1999)

  3. 3

    Rosenberg, E. S. et al. Immune control of HIV-1 after early treatment of acute infection. Nature 407, 523–526 (2000)

  4. 4

    Borrow, P., Lewicki, H., Hahn, B. H., Shaw, G. M. & Oldstone, M. B. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J. Virol. 68, 6103–6110 (1994)

  5. 5

    Jin, X. et al. Dramatic rise in plasma viremia after CD8+ T cell depletion in simian immunodeficiency virus-infected macaques. J. Exp. Med. 189, 991–998 (1999)

  6. 6

    Koup, R. A. et al. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J. Virol. 68, 4650–4655 (1994)

  7. 7

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

  8. 8

    Allen, T. M. et al. Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia. Nature 407, 386–390 (2000)

  9. 9

    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)

  10. 10

    Amara, R. R. et al. Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine. Science 292, 69–74 (2001)

  11. 11

    Shiver, J. W. et al. Replication-incompetent adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity. Nature 415, 331–335 (2002)

  12. 12

    Hanke, T. et al. Effective induction of simian immunodeficiency virus-specific cytotoxic T lymphocytes in macaques by using a multiepitope gene and DNA prime- modified vaccinia virus Ankara boost vaccination regimen. J. Virol. 73, 7524–7532 (1999)

  13. 13

    Allen, T. M. et al. Tat-vaccinated macaques do not control simian immunodeficiency virus SIVmac239 replication. J. Virol. 76, 4108–4112 (2002)

  14. 14

    Feinberg, M. B. & Moore, J. P. AIDS vaccine models: challenging challenge viruses. Nature Med. 8, 207–210 (2002)

  15. 15

    Malhotra, U. et al. Effect of combination antiretroviral therapy on T-cell immunity in acute human immunodeficiency virus type 1 infection. J. Infect. Dis. 181, 121–131 (2000)

  16. 16

    Oxenius, A. et al. Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of CD8+ and CD4+ T lymphocytes. Proc. Natl Acad. Sci. USA 97, 3382–3387 (2000)

  17. 17

    Douek, D. C. et al. HIV preferentially infects HIV-specific CD4+ T cells. Nature 417, 95–98 (2002)

  18. 18

    Barouch, D. H. et al. Eventual AIDS vaccine failure in a rhesus monkey by viral escape from cytotoxic T lymphocytes. Nature 415, 335–339 (2002)

  19. 19

    Yu, X. G. et al. Consistent patterns in the development and immunodominance of human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T-cell responses following acute HIV-1 infection. J. Virol. 76, 8690–8701 (2002)

  20. 20

    Montefiori, D. C., Hill, T. S., Vo, H. T., Walker, B. D. & Rosenberg, E. S. Neutralizing antibodies associated with viremia control in a subset of individuals after treatment of acute human immunodeficiency virus type 1 infection. J. Virol. 75, 10200–10207 (2001)

  21. 21

    Altfeld, M. A. et al. Identification of dominant optimal HLA-B60- and HLA-B61-restricted cytotoxic T-lymphocyte (CTL) epitopes: rapid characterization of CTL responses by enzyme-linked immunospot assay. J. Virol. 74, 8541–8549 (2000)

  22. 22

    Del Val, M., Schlicht, H. J., Ruppert, T., Reddehase, M. J. & Koszinowski, U. H. Efficient processing of an antigenic sequence for presentation by MHC class I molecules depends on its neighbouring residues in the protein. Cell 66, 1145–1153 (1991)

  23. 23

    Ramos, A. et al. Intersubtype human immunodeficiency virus type 1 superinfection following seroconversion to primary infection in two injection drug users. J. Virol. 76, 7444–7452 (2002)

  24. 24

    Jost, S. et al. A patient with HIV-1 superinfection. N. Engl. J. Med. 347, 731–736 (2002)

  25. 25

    McCutchan, F. E. Understanding the genetic diversity of HIV-1. Aids 14, S31–S44 (2000)

  26. 26

    Brander, C., Goulder, P. J. R., et al. HIV Molecular Database (ed. Korber, B. T. M.) I1–I20 (Los Alamos National Laboratory, Los Alamos, NM, 1999)

  27. 27

    Felsenstein, J. PHYLIP—Phylogeny Inference Package Version 3.5c, (Dept. Genetics, Univ. Washington, Seattle, 1989)

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Acknowledgements

We thank the Advanced Computing Laboratory at the Los Alamos National Lab for providing time on the Nirvana supercomputer for the maximum likelihood phylogenetic analysis, and Tanmoy Bhattacharya for his advice. This study was supported by the Doris Duke Charitable Foundation (M.A., E.S.R.,B.D.W.), the NIH (M.A., E.S.R., B.D.W.), the Foundation for AIDS & Immune Research (M.A.), and the Partners/Fenway/Shattuck Center for AIDS Research (T.A., X.G.Y.). B.D.W. is the recipient of a Doris Duke Distinguished Clinical Scientist Award; B.T.K. and P.J.R.G. are recipients of the Elizabeth Glaser Scientist Award.

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Correspondence to Bruce D. Walker.

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The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figures 1-3, Tables I-III (PDF 1108 kb)

Supplementary Figure Legends (DOC 24 kb)

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Further reading

Figure 1: HIV-1 viral loads, CD4+ T-cell counts and Gag-specific lymphoproliferative responses in study subject AC-06.
Figure 2: CD8+ T-cell responses to described optimal clade-B sequence cytotoxic T lymphocyte (CTL) epitopes during successive supervised treatment interruptions (STIs).
Figure 3: Sequence and phylogenetic analysis of viruses from subject AC-06.

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