Abstract

The acquired immunodeficiency syndrome (AIDS)-causing lentiviruses human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) effectively evade host immunity and, once established, infections with these viruses are only rarely controlled by immunological mechanisms1,2,3. However, the initial establishment of infection in the first few days after mucosal exposure, before viral dissemination and massive replication, may be more vulnerable to immune control4. Here we report that SIV vaccines that include rhesus cytomegalovirus (RhCMV) vectors5 establish indefinitely persistent, high-frequency, SIV-specific effector memory T-cell (TEM) responses at potential sites of SIV replication in rhesus macaques and stringently control highly pathogenic SIVMAC239 infection early after mucosal challenge. Thirteen of twenty-four rhesus macaques receiving either RhCMV vectors alone or RhCMV vectors followed by adenovirus 5 (Ad5) vectors (versus 0 of 9 DNA/Ad5-vaccinated rhesus macaques) manifested early complete control of SIV (undetectable plasma virus), and in twelve of these thirteen animals we observed long-term (≥1 year) protection. This was characterized by: occasional blips of plasma viraemia that ultimately waned; predominantly undetectable cell-associated viral load in blood and lymph node mononuclear cells; no depletion of effector-site CD4+ memory T cells; no induction or boosting of SIV Env-specific antibodies; and induction and then loss of T-cell responses to an SIV protein (Vif) not included in the RhCMV vectors. Protection correlated with the magnitude of the peak SIV-specific CD8+ T-cell responses in the vaccine phase, and occurred without anamnestic T-cell responses. Remarkably, long-term RhCMV vector-associated SIV control was insensitive to either CD8+ or CD4+ lymphocyte depletion and, at necropsy, cell-associated SIV was only occasionally measurable at the limit of detection with ultrasensitive assays, observations that indicate the possibility of eventual viral clearance. Thus, persistent vectors such as CMV and their associated TEM responses might significantly contribute to an efficacious HIV/AIDS vaccine.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , & in Persistent Viral Infections (eds & ) 3–45 (John Wiley & Sons, 1999)

  2. 2.

    Perils at mucosal front lines for HIV and SIV and their hosts. Nature Rev. Immunol. 5, 783–792 (2005)

  3. 3.

    & Impact of MHC class I diversity on immune control of immunodeficiency virus replication. Nature Rev. Immunol. 8, 619–630 (2008)

  4. 4.

    Targeting early infection to prevent HIV-1 mucosal transmission. Nature 464, 217–223 (2010)

  5. 5.

    et al. Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge. Nature Med. 15, 293–299 (2009)

  6. 6.

    & T cell vaccines for microbial infections. Nature Med. 11, S25–S32 (2005)

  7. 7.

    et al. Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc. Natl Acad. Sci. USA 105, 7552–7557 (2008)

  8. 8.

    et al. Early establishment of a pool of latently infected, resting CD4+ T cells during primary HIV-1 infection. Proc. Natl Acad. Sci. USA 95, 8869–8873 (1998)

  9. 9.

    , , & Protection against immunopathological consequences of a viral infection by activated but not resting cytotoxic T cells: T cell memory without “memory T cells”? Proc. Natl Acad. Sci. USA 94, 640–645 (1997)

  10. 10.

    et al. A comparison of T cell memory against the same antigen induced by virus versus intracellular bacteria. Proc. Natl Acad. Sci. USA 96, 9293–9298 (1999)

  11. 11.

    et al. Attenuation of simian immunodeficiency virus SIVmac239 infection by prophylactic immunization with dna and recombinant adenoviral vaccine vectors expressing Gag. J. Virol. 79, 15547–15555 (2005)

  12. 12.

    et al. Preserved CD4+ central memory T cells and survival in vaccinated SIV-challenged monkeys. Science 312, 1530–1533 (2006)

  13. 13.

    et al. Vaccine-induced cellular immune responses reduce plasma viral concentrations after repeated low-dose challenge with pathogenic simian immunodeficiency virus SIVmac239. J. Virol. 80, 5875–5885 (2006)

  14. 14.

    et al. Subdominant CD8+ T-cell responses are involved in durable control of AIDS virus replication. J. Virol. 81, 3465–3476 (2007)

  15. 15.

    et al. Macaques vaccinated with live-attenuated SIV control replication of heterologous virus. J. Exp. Med. 205, 2537–2550 (2008)

  16. 16.

    et al. Resting CD4+ T lymphocytes but not thymocytes provide a latent viral reservoir in a simian immunodeficiency virus-Macaca nemestrina model of human immunodeficiency virus type 1-infected patients on highly active antiretroviral therapy. J. Virol. 77, 4938–4949 (2003)

  17. 17.

    et al. A simian immunodeficiency virus-infected macaque model to study viral reservoirs that persist during highly active antiretroviral therapy. J. Virol. 83, 9247–9257 (2009)

  18. 18.

    et al. Viral sanctuaries during highly active antiretroviral therapy in a nonhuman primate model for AIDS. J. Virol. 84, 2913–2922 (2010)

  19. 19.

    et al. Protease inhibitor-containing regimens compared with nucleoside analogues alone in the suppression of persistent HIV-1 replication in lymphoid tissue. AIDS 13, F1–F8 (1999)

  20. 20.

    et al. Isolation and characterization of replication-competent human immuno-deficiency virus type 1 from a subset of elite suppressors. J. Virol. 81, 2508–2518 (2007)

  21. 21.

    et al. Multiple measures of HIV burden in blood and tissue are correlated with each other but not with clinical parameters in aviremic subjects. AIDS 17, 53–63 (2003)

  22. 22.

    Evaluating neutralizing antibodies against HIV, SIV, and SHIV in luciferase reporter gene assays. Curr. Protoc. Immunol. 12, Unit 12.11. (2005)

  23. 23.

    , , & Highly sensitive SIV plasma viral load assay: practical considerations, realistic performance expectations, and application to reverse engineering of vaccines for AIDS. J. Med. Primatol. 34, 303–312 (2005)

  24. 24.

    et al. Longitudinal in vivo positron emission tomography imaging of infected and activated brain macrophages in a macaque model of human immunodeficiency virus encephalitis correlates with central and peripheral markers of encephalitis and areas of synaptic degeneration. Am. J. Pathol. 172, 1603–1616 (2008)

  25. 25.

    et al. Profound CD4+/CCR5+ T cell expansion is induced by CD8+ lymphocyte depletion but does not account for accelerated SIV pathogenesis. J. Exp. Med. 206, 1575–1588 (2009)

  26. 26.

    et al. Reduced protection from simian immunodeficiency virus SIVmac251 infection afforded by memory CD8+ T cells induced by vaccination during CD4+ T-cell deficiency. J. Virol. 82, 9629–9638 (2008)

  27. 27.

    et al. Development and homeostasis of T cell memory in rhesus macaque. J. Immunol. 168, 29–43 (2002)

  28. 28.

    et al. Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science 280, 427–431 (1998)

  29. 29.

    et al. Simian immunodeficiency virus (SIV)-specific CTL are present in large numbers in livers of SIV-infected rhesus monkeys. J. Immunol. 164, 6015–6019 (2000)

  30. 30.

    & Cloning of the full-length rhesus cytomegalovirus genome as an infectious and self-excisable bacterial artificial chromosome for analysis of viral pathogenesis. J. Virol. 77, 5073–5083 (2003)

  31. 31.

    et al. Comparison of immune responses generated by optimized DNA vaccination against SIV antigens in mice and macaques. Vaccine doi:10.1016/j.vaccine.2010.12.056.

  32. 32.

    et al. DNA vaccines expressing different forms of simian immunodeficiency virus antigens decrease viremia upon SIVmac251 challenge. J. Virol. 79, 8480–8492 (2005)

  33. 33.

    et al. DNA vaccination in rhesus macaques induces potent immune responses and decreases acute and chronic viremia after SIVmac251 challenge. Proc. Natl Acad. Sci. USA 106, 15831–15836 (2009)

  34. 34.

    et al. In vivo transfer of the human cystic fibrosis transmembrane conductance regulator gene to the airway epithelium. Cell 68, 143–155 (1992)

  35. 35.

    , & Evaluation of the concentration and bioactivity of adenovirus vectors for gene therapy. J. Virol. 70, 7498–7509 (1996)

  36. 36.

    et al. Novel pathway for induction of latent virus from resting CD4+ T cells in the simian immunodeficiency virus/macaque model of human immunodeficiency virus type 1 latency. J. Virol. 81, 1660–1670 (2007)

Download references

Acknowledgements

This work was supported by the National Institute of Allergy and Infectious Diseases (RO1 AI060392; contract #HHSN272200900037C); the International AIDS Vaccine Initiative (IAVI) and its donors, particularly the United States Agency for International Development (USAID); the Bill & Melinda Gates Foundation-supported Collaboration for AIDS Vaccine Discovery; the National Center for Research Resources (P51 RR00163; R24 RR016001); and the National Cancer Institute (contract HHSN261200800001E). We thank A. Sylwester, D. Seiss, R. Lum, H. Park and A. Okoye for specialized technical assistance; P. Barry, G. Pavlakis, G. Franchini, C. Miller, N. Wilson, and K. Reimann and Nonhuman Primate Reagent Resource for provision of crucial constructs or reagents; D. Watkins for MHC typing; D. Montefiori for neutralizing antibody assays; N. Letvin and L. Shen for TRIM5a typing; S. Mongoue-Tchokote and M. Mori for statistical assistance; A. Townsend and T. Schroyer for figure preparation; and K. Früh, D. Watkins, B. Beresford, A. McDermott, R. King and W. Koff for discussion and advice.

Author information

Affiliations

  1. Vaccine and Gene Therapy Institute, Departments of Molecular Microbiology and Immunology and Pathology, and the Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, USA

    • Scott G. Hansen
    • , Julia C. Ford
    • , Matthew S. Lewis
    • , Abigail B. Ventura
    • , Colette M. Hughes
    • , Lia Coyne-Johnson
    • , Nathan Whizin
    • , Tonya Swanson
    • , Alfred W. Legasse
    • , Michael K. Axthelm
    • , Jay A. Nelson
    • , Michael A. Jarvis
    •  & Louis J. Picker
  2. AIDS and Cancer Virus Program, SAIC Frederick Inc., National Cancer Institute-Frederick, Frederick, Maryland 21702, USA

    • Kelli Oswald
    • , Rebecca Shoemaker
    • , Michael Piatak
    •  & Jeffrey D. Lifson
  3. International AIDS Vaccine Initiative, Vaccine Design and Development Laboratory, 140 58th Street, Building A, Unit 8J, Brooklyn, New York 11220, USA

    • Maria J. Chiuchiolo
    •  & Christopher L. Parks

Authors

  1. Search for Scott G. Hansen in:

  2. Search for Julia C. Ford in:

  3. Search for Matthew S. Lewis in:

  4. Search for Abigail B. Ventura in:

  5. Search for Colette M. Hughes in:

  6. Search for Lia Coyne-Johnson in:

  7. Search for Nathan Whizin in:

  8. Search for Kelli Oswald in:

  9. Search for Rebecca Shoemaker in:

  10. Search for Tonya Swanson in:

  11. Search for Alfred W. Legasse in:

  12. Search for Maria J. Chiuchiolo in:

  13. Search for Christopher L. Parks in:

  14. Search for Michael K. Axthelm in:

  15. Search for Jay A. Nelson in:

  16. Search for Michael A. Jarvis in:

  17. Search for Michael Piatak in:

  18. Search for Jeffrey D. Lifson in:

  19. Search for Louis J. Picker in:

Contributions

S.G.H. planned and performed experiments and analysed data, assisted by J.C.F., M.S.L., A.B.V., C.M.H., L.C.-J. and N.W. T.S., A.W.L. and M.K.A. managed the animal protocols. M.A.J. designed, constructed and characterized the RhCMV vectors. M.P. Jr and J.D.L. planned and performed SIV quantification studies, assisted by K.O. and R.S. C.L.P. and M.J.C. designed and constructed the DNA and Ad5 vectors used in this study. J.A.N. was involved in conception of the RhCMV vector strategy. L.J.P. conceived the RhCMV vector strategy, supervised experiments, analysed data and wrote the paper, assisted by S.G.H., M.A.J. and J.D.L.

Competing interests

[Competing financial interests: OHSU has licensed CMV vector technology, for which L.J.P., M.A.J. and J.A.N. are inventors, to the International AIDS Vaccine Initiative (IAVI).]

Corresponding author

Correspondence to Louis J. Picker.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Figures 1-15 with legends, Supplementary Table 1, a Supplementary Discussion and additional references.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature10003

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.