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Lymph node T cell responses predict the efficacy of live attenuated SIV vaccines

Abstract

Live attenuated simian immunodeficiency virus (SIV) vaccines (LAVs) remain the most efficacious of all vaccines in nonhuman primate models of HIV and AIDS, yet the basis of their robust protection remains poorly understood. Here we show that the degree of LAV-mediated protection against intravenous wild-type SIVmac239 challenge strongly correlates with the magnitude and function of SIV-specific, effector-differentiated T cells in the lymph node but not with the responses of such T cells in the blood or with other cellular, humoral and innate immune parameters. We found that maintenance of protective T cell responses is associated with persistent LAV replication in the lymph node, which occurs almost exclusively in follicular helper T cells. Thus, effective LAVs maintain lymphoid tissue-based, effector-differentiated, SIV-specific T cells that intercept and suppress early wild-type SIV amplification and, if present in sufficient frequencies, can completely control and perhaps clear infection, an observation that provides a rationale for the development of safe, persistent vectors that can elicit and maintain such responses.

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Figure 1: LAV virology and differential efficacy.
Figure 2: Immunological correlates of LAV-mediated protection.
Figure 3: Association of tissue LAV replication and SIV-specific T cell responses.
Figure 4: Transcriptional profiling of unfractionated lymph node cells before and after wild-type SIV challenge.
Figure 5: Transcriptional profiling of sorted lymph node CD8+ T cells at days 4 and 14 after wild-type SIV challenge (PCD 4 and PCD 14).

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References

  1. Daniel, M.D., Kirchhoff, F., Czajak, S.C., Sehgal, P.K. & Desrosiers, R.C. Protective effects of a live attenuated SIV vaccine with a deletion in the nef gene. Science 258, 1938–1941 (1992).

    Article  CAS  PubMed  Google Scholar 

  2. Johnson, R.P. & Desrosiers, R.C. Protective immunity induced by live attenuated simian immunodeficiency virus. Curr. Opin. Immunol. 10, 436–443 (1998).

    Article  CAS  PubMed  Google Scholar 

  3. Koff, W.C. et al. HIV vaccine design: insights from live attenuated SIV vaccines. Nat. Immunol. 7, 19–23 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Picker, L.J., Hansen, S.G. & Lifson, J.D. New paradigms for HIV/AIDS vaccine development. Annu. Rev. Med. 63, 95–111 (2012).

    Article  CAS  PubMed  Google Scholar 

  5. Abel, K. et al. Simian-human immunodeficiency virus SHIV89.6-induced protection against intravaginal challenge with pathogenic SIVmac239 is independent of the route of immunization and is associated with a combination of cytotoxic T-lymphocyte and α interferon responses. J. Virol. 77, 3099–3118 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Sugimoto, C. et al. Protection of macaques with diverse MHC genotypes against a heterologous SIV by vaccination with a deglycosylated live-attenuated SIV. PLoS ONE 5, e11678 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Whitney, J.B. & Ruprecht, R.M. Live attenuated HIV vaccines: pitfalls and prospects. Curr. Opin. Infect. Dis. 17, 17–26 (2004).

    Article  PubMed  Google Scholar 

  8. Metzner, K.J. et al. Effects of in vivo CD8+ T cell depletion on virus replication in rhesus macaques immunized with a live, attenuated simian immunodeficiency virus vaccine. J. Exp. Med. 191, 1921–1931 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Stebbings, R. et al. Vaccination with live attenuated simian immunodeficiency virus for 21 days protects against superinfection. Virology 330, 249–260 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Stebbings, R. et al. CD8+ lymphocytes do not mediate protection against acute superinfection 20 days after vaccination with a live attenuated simian immunodeficiency virus. J. Virol. 79, 12264–12272 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Nethe, M., Berkhout, B. & van der Kuyl, A.C. Retroviral superinfection resistance. Retrovirology 2, 52 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Schmitz, J.E. et al. Effect of CD8+ lymphocyte depletion on virus containment after simian immunodeficiency virus SIVmac251 challenge of live attenuated SIVmac239Δ3-vaccinated rhesus macaques. J. Virol. 79, 8131–8141 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mansfield, K. et al. Vaccine protection by live, attenuated simian immunodeficiency virus in the absence of high-titer antibody responses and high-frequency cellular immune responses measurable in the periphery. J. Virol. 82, 4135–4148 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Genescà, M. et al. With minimal systemic T-cell expansion, CD8+ T cells mediate protection of rhesus macaques immunized with attenuated simian-human immunodeficiency virus SHIV89.6 from vaginal challenge with simian immunodeficiency virus. J. Virol. 82, 11181–11196 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Reynolds, M.R. et al. Macaques vaccinated with simian immunodeficiency virus SIVmac239Δ nef delay acquisition and control replication after repeated low-dose heterologous SIV challenge. J. Virol. 84, 9190–9199 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Haase, A.T. Early events in sexual transmission of HIV and SIV and opportunities for interventions. Annu. Rev. Med. 62, 127–139 (2011).

    Article  CAS  PubMed  Google Scholar 

  18. Johnson, R.P. et al. Highly attenuated vaccine strains of simian immunodeficiency virus protect against vaginal challenge: inverse relationship of degree of protection with level of attenuation. J. Virol. 73, 4952–4961 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Jia, B. et al. Immunization with single-cycle SIV significantly reduces viral loads after an intravenous challenge with SIV(mac)239. PLoS Pathog. 5, e1000272 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Kirmaier, A. et al. TRIM5 suppresses cross-species transmission of a primate immunodeficiency virus and selects for emergence of resistant variants in the new species. PLoS Biol. 8, e1000462 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Crotty, S. Follicular helper CD4 T cells (TFH). Annu. Rev. Immunol. 29, 621–663 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Ma, C.S. et al. Early commitment of naive human CD4+ T cells to the T follicular helper (TFH) cell lineage is induced by IL-12. Immunol. Cell Biol. 87, 590–600 (2009).

    Article  CAS  PubMed  Google Scholar 

  23. Hong, J.J., Amancha, P.K., Rogers, K., Ansari, A.A. & Villinger, F. Spatial alterations between CD4+ T follicular helper, B, and CD8+ T cells during simian immunodeficiency virus infection: T/B cell homeostasis, activation, and potential mechanism for viral escape. J. Immunol. 188, 3247–3256 (2012).

    Article  CAS  PubMed  Google Scholar 

  24. Sugimoto, C. et al. nef gene is required for robust productive infection by simian immunodeficiency virus of T-cell–rich paracortex in lymph nodes. J. Virol. 77, 4169–4180 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. West, E.E. et al. Tight regulation of memory CD8+ T cells limits their effectiveness during sustained high viral load. Immunity 35, 285–298 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kallies, A. Distinct regulation of effector and memory T-cell differentiation. Immunol. Cell Biol. 86, 325–332 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Intlekofer, A.M. et al. Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin. Nat. Immunol. 6, 1236–1244 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Taylor, J.J. & Jenkins, M.K. CD4+ memory T cell survival. Curr. Opin. Immunol. 23, 319–323 (2011).

    Article  CAS  PubMed  Google Scholar 

  29. Kersse, K., Lamkanfi, M., Bertrand, M.J., Vanden Berghe, T. & Vandenabeele, P. Interaction patches of procaspase-1 caspase recruitment domains (CARDs) are differently involved in procaspase-1 activation and receptor-interacting protein 2 (RIP2)-dependent nuclear factor κB signaling. J. Biol. Chem. 286, 35874–35882 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Verdeil, G., Puthier, D., Nguyen, C., Schmitt-Verhulst, A.-M. & Auphan-Anezin, N. STAT5-mediated signals sustain a TCR-initiated gene expression program toward differentiation of CD8 T cell effectors. J. Immunol. 176, 4834–4842 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Coller, H.A., Sang, L. & Roberts, J.M. A new description of cellular quiescence. PLoS Biol. 4, e83 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Sacha, J.B. et al. Gag- and Nef-specific CD4+ T cells recognize and inhibit SIV replication in infected macrophages early after infection. Proc. Natl. Acad. Sci. USA 106, 9791–9796 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sant, A.J. & McMichael, A. Revealing the role of CD4+ T cells in viral immunity. J. Exp. Med. 209, 1391–1395 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hansen, S.G. et al. Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine. Nature 473, 523–527 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Haynes, B.F. et al. Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N. Engl. J. Med. 366, 1275–1286 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Barouch, D.H. et al. Vaccine protection against acquisition of neutralization-resistant SIV challenges in rhesus monkeys. Nature 482, 89–93 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Vezys, V. et al. Memory CD8 T-cell compartment grows in size with immunological experience. Nature 457, 196–199 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  39. Grossman, Z. & Picker, L.J. Pathogenic mechanisms in simian immunodeficiency virus infection. Curr. Opin. HIV AIDS 3, 380–386 (2008).

    Article  PubMed  Google Scholar 

  40. Shen, A. 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).

    Article  CAS  PubMed  Google Scholar 

  41. Chackerian, B., Haigwood, N.L. & Overbaugh, J. Characterization of a CD4-expressing macaque cell line that can detect virus after a single replication cycle and can be infected by diverse simian immunodeficiency virus isolates. Virology 213, 386–394 (1995).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  43. Schmitz, J.E. 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).

    Article  CAS  PubMed  Google Scholar 

  44. Cline, A.N., Bess, J.W., Piatak, M. Jr. & Lifson, J.D. 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).

    Article  CAS  PubMed  Google Scholar 

  45. Venneti, S. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Salisch, N.C. et al. Inhibitory TCR coreceptor PD-1 is a sensitive indicator of low-level replication of SIV and HIV-1. J. Immunol. 184, 476–487 (2010).

    Article  CAS  PubMed  Google Scholar 

  47. Martins, M.A. et al. T-cell correlates of vaccine efficacy after a heterologous simian immunodeficiency virus challenge. J. Virol. 84, 4352–4365 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hansen, S.G. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Walker, J.M., Maecker, H.T., Maino, V.C. & Picker, L.J. Multicolor flow cytometric analysis in SIV-infected rhesus macaque. Methods Cell Biol. 75, 535–557 (2004).

    Article  PubMed  Google Scholar 

  50. Picker, L.J. et al. IL-15 induces CD4 effector memory T cell production and tissue emigration in nonhuman primates. J. Clin. Invest. 116, 1514–1524 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Picker, L.J. et al. Control of lymphocyte recirculation in man. I. Differential regulation of the peripheral lymph node homing receptor L-selectin on T cells during the virgin to memory cell transition. J. Immunol. 150, 1105–1121 (1993).

    CAS  PubMed  Google Scholar 

  52. Todd, C.A. et al. Development and implementation of an international proficiency testing program for a neutralizing antibody assay for HIV-1 in TZM-bl cells. J. Immunol. Methods 375, 57–67 (2012).

    Article  CAS  PubMed  Google Scholar 

  53. Pollara, J. et al. High-throughput quantitative analysis of HIV-1 and SIV-specific ADCC-mediating antibody responses. Cytometry A 79, 603–612 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  54. R Core Team. R: a language and environment for statistical computing. <http://www.r-project.org/> (2011).

  55. Gentleman, R.C. et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 5, R80 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Smyth, G.K. Linear models and empirical Bayes methods for assessing differential expression in microarray experiments. Stat. Appl. Genet. Mol. Biol. 3, 3 (2004).

    Article  Google Scholar 

  57. Caskey, M. et al. Synthetic double-stranded RNA induces innate immune responses similar to a live viral vaccine in humans. J. Exp. Med. 208, 2357–2366 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Wolfe, D.A. & Hollander, M. Nonparametric Statistical Methods. (Wiley, New York, 1973).

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Acknowledgements

This work was supported by the Bill and Melinda Gates Foundation (grant #41185), the International AIDS Vaccine Initiative (IAVI), the National Institute of Allergy and Infectious Diseases (including the US National Institutes of Health (NIH) grant R37 AI054292 (L.J.P.), contract HHSN272200900037C and the Center for HIV-AIDS Vaccine Immunology (CHAVI) program), the NIH Office of Research Infrastructure Programs (P51 OD 011092) and the National Cancer Institute (contract HHSN261200800001E). The authors acknowledge R. Desrosiers (Harvard University) for providing SIVmac239Δnef and SIVmac239Δ3; P. Johnson and T. Lui (University of Pennsylvania) for SIVsmE543Δnef; C. Miller (University of California, Davis) for SHIV89.6 and wild-type SIVmac239; D. Evans (Harvard University) for a single-cycle SIVmac239; N. Letvin for TRIM5 allele typing; and R. Wiseman and D. Watkins for MHC typing. We thank N. Winstone, A. Leon, J. Clock, A. Nogueron, L. Pan, M. Cartwright, A. Filali and P. Wilkinson for technical assistance and J. McElrath, S. Self, W. Koff, A. Okoye, J. Schmitz and J. Ahler for helpful discussion and advice.

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Y.F., R.L., N.C., E.M., S.I.H. and S.G.H. performed experiments and analyzed data, assisted by M.D.R. and J.Y.B. H.P. managed the project and analyzed data, assisted by A.S. T.S., A.W.L. and M.K.A. managed the animal protocols. M.P. and J.D.L. provided SIV and LAV quantifications, assisted by R.S., Y.L. and K.O. D.C.M. and G.F. provided neutralizing antibodies and cytotoxic antibody quantification, respectively. M.J.C., F.L., A.T.S., P.S. and R.P.S. carried out the microarray analysis and interpreted the results. P.T.E. performed the statistical analysis. L.J.P. conceived of the study, supervised experiments, analyzed data and wrote the paper, assisted by Y.F., H.P., P.T.E., A.M., R.P.S. and J.D.L.

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Correspondence to Louis J Picker.

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Fukazawa, Y., Park, H., Cameron, M. et al. Lymph node T cell responses predict the efficacy of live attenuated SIV vaccines. Nat Med 18, 1673–1681 (2012). https://doi.org/10.1038/nm.2934

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