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Mucosal AIDS vaccine reduces disease and viral load in gut reservoir and blood after mucosal infection of macaques

Nature Medicine volume 7, pages 1320–1326 (2001)Cite this article

Abstract

Given the mucosal transmission of HIV-1, we compared whether a mucosal vaccine could induce mucosal cytotoxic T lymphocytes (CTLs) and protect rhesus macaques against mucosal infection with simian/human immunodeficiency virus (SHIV) more effectively than the same vaccine given subcutaneously. Here we show that mucosal CTLs specific for simian immunodeficiency virus can be induced by intrarectal immunization of macaques with a synthetic-peptide vaccine incorporating the LT(R192G) adjuvant. This response correlated with the level of T-helper response. After intrarectal challenge with pathogenic SHIV-Ku2, viral titers were eliminated more completely (to undetectable levels) both in blood and intestine, a major reservoir for virus replication, in intrarectally immunized animals than in subcutaneously immunized or control macaques. Moreover, CD4+ T cells were better preserved. Thus, induction of CTLs in the intestinal mucosa, a key site of virus replication, with a mucosal AIDS vaccine ameliorates infection by SHIV in non-human primates.

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Figure 1: Synthetic HIV/SIV vaccine constructs used for the immunizations, and scheme of immunization and challenge.
Figure 2: Induction of CTLs specific for SIV Gag CL10, Gag 372 or Pol 143, as indicated, in MLN, colonic lamina propria, PBMCs and ALN of group C macaques after 8 intrarectal immunizations with HIV/SIV peptide and LT(R192G).
Figure 3: Induction of CL10 SIV Gag-specific CTLs in ALN, MLN and PBMC and SIV Pol 143- and SIV Gag 372-specific CTLs in ALN of group B macaques after 8 s.c. immunizations with HIV/SIV peptide in Montanide ISA 51.
Figure 4: Helper T-cell response correlates with CTL response.
Figure 5: Intrarectal and s.c. immunization of macaques with HIV/SIV peptide vaccine differentially protect against intrarectal challenge with pathogenic SHIV-Ku2.
Figure 6: Intrarectal peptide vaccine was more effective than s.c. peptide vaccine at priming colonic CTLs for a secondary response induced by challenge infection with SHIV, and clearing virus from the gut.

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Acknowledgements

We thank M. Spano and the animal care staff at the ABL for their assistance; R. Pal for the titered stock of SHIV-Ku2; J.-P. Planchot for the Montanide ISA51; M. Lewis for the DNA PCR of provirus; V. Stepanov, Y. Tuyrin, S. Steinberg, D. Venzon and E. Brunner for assistance, advice and critical comments on statistical analysis; V. Hirsch, B. Moss, and J. Snyder for critical reading of the manuscript and helpful suggestions; and N. Miller for support of the animals. The work of A.S. was partially supported by NIH contract N01-AI-95362 and grant R24 RR 15731.

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Authors and Affiliations

  1. Molecular Immunogenetics and Vaccine Research Section, Metabolism Branch, National Cancer Institute, Bethesda, Maryland, USA

    Igor M. Belyakov, Jeffrey D. Ahlers & Jay A. Berzofsky

  2. Animal Model and Retroviral Vaccines Section, Basic Research Laboratory, National Cancer Institute, Bethesda, Maryland, USA

    Zdenek Hel, Janos Nacsa & Genoveffa Franchini

  3. Mucosal Immunity Section, Laboratory Of Clinical Investigation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA

    Brian Kelsall & Warren Strober

  4. Section of Medical Biophysics, Laboratory of Integrative and Medical Biophysics, National Institute of Child Health and Human Development, Bethesda, Maryland, USA

    Vladimir A. Kuznetsov

  5. Wisconsin Regional Primate Research Center, Madison, Wisconsin, USA

    David I. Watkins & Todd M. Allen

  6. Epimmune, San Diego, California, USA

    Alessandro Sette

  7. Emory University Vaccine Center at Yerkes, Atlanta, Georgia, USA

    John Altman

  8. Advanced BioScience Laboratories, Kensington, Maryland, USA

    Ruth Woodward & Phillip D. Markham

  9. Department of Microbiology and Immunology, Program in Molecular Pathogenesis and Immunity, Tulane University School of Medicine, New Orleans, Louisiana, USA

    John D. Clements

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  1. Igor M. Belyakov
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Correspondence to Igor M. Belyakov or Jay A. Berzofsky.

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Belyakov, I., Hel, Z., Kelsall, B. et al. Mucosal AIDS vaccine reduces disease and viral load in gut reservoir and blood after mucosal infection of macaques. Nat Med 7, 1320–1326 (2001). https://doi.org/10.1038/nm1201-1320

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