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Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge

Nature Medicine volume 15, pages 293–299 (2009)Cite this article

An Addendum to this article was published on 06 December 2011

A Corrigendum to this article was published on 01 April 2009

This article has been updated

Abstract

The rapid onset of massive, systemic viral replication during primary HIV or simian immunodeficiency virus (SIV) infection and the immune evasion capabilities of these viruses pose fundamental problems for vaccines that depend upon initial viral replication to stimulate effector T cell expansion and differentiation1,2,3,4,5. We hypothesized that vaccines designed to maintain differentiated effector memory T cell (TEM cell) responses5,6 at viral entry sites might improve efficacy by impairing viral replication at its earliest stage2, and we have therefore developed SIV protein-encoding vectors based on rhesus cytomegalovirus (RhCMV), the prototypical inducer of life-long TEM cell responses7,8,9. RhCMV vectors expressing SIV Gag, Rev-Tat-Nef and Env persistently infected rhesus macaques, regardless of preexisting RhCMV immunity, and primed and maintained robust, SIV-specific CD4+ and CD8+ TEM cell responses (characterized by coordinate tumor necrosis factor, interferon-γ and macrophage inflammatory protein-1β expression, cytotoxic degranulation and accumulation at extralymphoid sites) in the absence of neutralizing antibodies. Compared to control rhesus macaques, these vaccinated rhesus macaques showed increased resistance to acquisition of progressive SIVmac239 infection upon repeated limiting-dose intrarectal challenge, including four macaques who controlled rectal mucosal infection without progressive systemic dissemination. These data suggest a new paradigm for AIDS vaccine development—vaccines capable of generating and maintaining HIV-specific TEM cells might decrease the incidence of HIV acquisition after sexual exposure.

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Figure 1: RhCMV vectors engineered to express SIV proteins can re-infect RhCMV+ rhesus macaques and initiate a de novo SIV-specific CD4+ and CD8+ T cell response.
Figure 2: RhCMV-vectored, SIV-specific T cell responses persist with a polarized TEM phenotype and maintain high representation at extralymphoid effector sites.
Figure 3: RhCMV-vectored, SIV-specific T cell responses maintain potent effector function.
Figure 4: Rhesus macaques inoculated with RhCMV vectors expressing SIV Gag, a Rev-Tat-Nef fusion protein and Env are protected from progressive SIVmac239 infection after repeated limiting-dose intrarectal challenge.
Figure 5
Figure 6: Comparison of amino acid sequences of Retanef(Hel) and Retanef(int)

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Change history

  • 06 April 2009

    In the version of this article initially published, a “left” and “right” designation was switched in the legend for Figure 4d. The legend should read “FCICA of peripheral blood CD8+ T cells from the four protected vaccinees, examining the response of these cells to SIV proteins that were (Rev-Tat-Nef) or were not (Pol and Vif) expressed by the administered RhCMV vectors before (left) and 133 d after (right) initiation of the SIVmac239 intrarectal challenge protocol.” The error has been corrected in the HTML and PDF versions of the article.

  • 07 November 2011

     In Supplementary Figure 1 of our paper, the reference cited (Hel et al. in Vaccine 20, 3171–3186, 2002) and the description for the Retanef fusion gene expressed by RhCMV-Retanef were incorrect. The correct description for the fusion gene (here designated Retanef(int)) and citation are now contained in the Supplementary Information. Retanef(int) is a fusion comprised of simian immunodeficiency virus (SIV) rev (Met1–Leu19), int (Lys159–Ala293), full-length nef (starting at Ala4) and tat (Glu2–Arg82), mutagenized to decrease toxicity, essentially as previously described by Kulkarni et al. (Vaccine 29, 6742–6754, 2011). Table 1 shows a comparison between Retanef(Hel) (Vaccine 20, 3171–3186, 2002) and our Retanef(int) construct. In Figure 4d of our paper, the appearance of de novo CD8+ T cell responses to overlapping peptides comprising the full-length SIV pol protein in the four stringently protected RhCMV-SIV–vaccinated rhesus macaques after SIVmac239 challenge was used as evidence of occult SIV infection. Although the presence of a pol component—int(Lys159–Ala293)—within the RhCMV-Retanef(int) vector would bring this conclusion into question, several lines of evidence strongly support our original interpretation. First, as we initially indicated, two of the four protected rhesus macaques showed transient SIV viremia, and all four of these rhesus macaques showed the appearance of de novo CD8+ responses to peptides comprising full-length SIV vif (a protein not included in the vaccine). Second, peripheral blood mononuclear cells from a total of 23 RhCMV-Retanef(int)–vaccinated and three SIV-infected rhesus macaques were found to be negative for both CD4+ and CD8+ T cell responses to peptide mixes comprising int (Lys159–Ala293), indicating this region is poorly immunogenic or nonimmunogenic for T cells in rhesus macaques. Finally, further analysis of cryopreserved T cells from the four protected monkeys in our study specifically shows the absence of CD8+ T cell responses to full-length pol, int(Lys159–Ala293) and the SIV rev/tat regions unique to the retanef(Hel) construct (and not in the RhCMV-retanef(int) vector administered to these rhesus macaques) prior to SIVmac239 challenge, as well as the appearance of such responses to full-length pol and the unique retanef(Hel) regions, but not the int(Lys159–Ala293), in all monkeys after SIV challenge (Fig. 1). Thus, challenge was associated with the induction of de novo CD8+ T cell responses to multiple distinct SIV sequences that were not included in the vaccine (that is, full-length vif, pol other than int(Lys159–Ala293), rev(Leu20–Asp100) and tat(Arg83–Arg131)), consistent, as we originally suggested, with controlled SIV infection. Thus, none of the conclusions of our original report are affected by the use of RhCMV-Retanef(int) reported in this addendum. (See PDF)

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Acknowledgements

This work was supported by the US National Institute of Allergy and Infectious Diseases, the International AIDS Vaccine Initiative, the Bill & Melinda Gates Foundation–supported Collaboration for AIDS Vaccine Discovery, the US National Center for Research Resources and the US National Cancer Institute. We thank J. Edgar, A. Keech, J. Ford, J. Cook, M. Rohankhedkar, T. Ha, A. Sylwester and J. Dewane for technical assistance; P. Barry (University of California–Davis) for the RhCMV bacterial artificial chromosome, G. Pavlakis (National Cancer Institute) for the SIV Gag and Env constructs, G. Franchini (National Cancer Institute) for the SIV Retanef construct, R. Seder (Vaccine Research Center, National Institutes of Health) for the Gag protein immunogens, C. Miller (University of California–Davis) for the pathogenic SIVmac239 challenge stock, K. Reimann and Centocor for the cM-T807 antibody, M. Mori and J. O'Malley for statistical assistance and K. Frueh and S. Wong for helpful discussion and advice.

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Authors and Affiliations

  1. Departments of Molecular Microbiology and Immunology and Pathology, Vaccine and Gene Therapy Institute, and the Oregon National Primate Research Center, Oregon Health & Science University, 505 Northwest 185th Avenue, Beaverton, 97006, Oregon, USA

    Scott G Hansen, Cassandra Vieville, Nathan Whizin, Lia Coyne-Johnson, Don C Siess, Derek D Drummond, Alfred W Legasse, Michael K Axthelm, Jay A Nelson, Michael A Jarvis & Louis J Picker

  2. AIDS and Cancer Virus Program, Science Applications International Corporation Frederick, National Cancer Institute–Frederick, 1050 Boyles Street, Building 535, Suite 510, Frederick, 21702, Maryland, USA

    Kelli Oswald, Charles M Trubey, Michael Piatak Jr & Jeffrey D Lifson

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Contributions

S.G.H., assisted by C.V., N.W., D.C.S. and L.C.-J., planned and performed experiments and analyzed data. A.W.L. and M.K.A. managed the animal protocols. M.A.J. designed, constructed and characterized the RhCMV vectors, assisted by D.D.D. M.P. and J.D.L., assisted by K.O. and C.M.T., planned and performed SIV quantification studies. J.A.N. was involved in conception of the RhCMV vector strategy. L.J.P. conceived the RhCMV vector strategy, supervised experiments, analyzed data and wrote the paper (assisted by M.A.J.).

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Correspondence to Louis J Picker.

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Hansen, S., Vieville, C., Whizin, N. et al. Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge. Nat Med 15, 293–299 (2009). https://doi.org/10.1038/nm.1935

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