Vaccine-induced myeloid cell population dampens protective immunity to SIV
Yongjun Sui, … , Genoveffa Franchini, Jay A. Berzofsky
Yongjun Sui, … , Genoveffa Franchini, Jay A. Berzofsky
Published May 16, 2014
Citation Information: J Clin Invest. 2014;124(6):2538-2549. https://doi.org/10.1172/JCI73518.
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Research Article

Vaccine-induced myeloid cell population dampens protective immunity to SIV

Abstract

Vaccines are largely evaluated for their ability to promote adaptive immunity, with little focus on the induction of negative immune regulators. Adjuvants facilitate and enhance vaccine-induced immune responses and have been explored for mediating protection against HIV. Using a regimen of peptide priming followed by a modified vaccinia Ankara (MVA) boost in a nonhuman primate model, we found that an SIV vaccine incorporating molecular adjuvants mediated partial protection against rectal SIVmac251 challenges. Animals treated with vaccine and multiple adjuvants exhibited a reduced viral load (VL) compared with those treated with vaccine only. Surprisingly, animals treated with adjuvant alone had reduced VLs that were comparable to or better than those of the vaccine-treated group. VL reduction was greatest in animals with the MHC class I allele Mamu-A*01 that were treated with adjuvant only and was largely dependent on CD8+ T cells. Early VLs correlated with Ki67+CCR5+CD4+ T cell frequency, while set-point VL was associated with expansion of a myeloid cell population that was phenotypically similar to myeloid-derived suppressor cells (MDSCs) and that suppressed T cell responses in vitro. MDSC expansion occurred in animals receiving vaccine and was not observed in the adjuvant-only group. Collectively, these results indicate that vaccine-induced MDSCs inhibit protective cellular immunity and suggest that preventing MDSC induction may be critical for effective AIDS vaccination.

Authors

Yongjun Sui, Alison Hogg, Yichuan Wang, Blake Frey, Huifeng Yu, Zheng Xia, David Venzon, Katherine McKinnon, Jeremy Smedley, Mercy Gathuka, Dennis Klinman, Brandon F. Keele, Sol Langermann, Linda Liu, Genoveffa Franchini, Jay A. Berzofsky

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Figure 3

Early and peak VLs inversely correlated with Gag-specific CD4+ T cell responses and positively correlated with immune activation status of the postvaccinated colonic tissue.

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Early and peak VLs inversely correlated with Gag-specific CD4+ T cell re...
(A) Comparison of vaccine-induced IL-2+CD3+CD4+ T cell frequency in the colonic LP 3 weeks after the last boost (n = 26). (B) IL-2+CD3+CD4+ T cell frequency in the colonic LP 3 weeks after the last boost was inversely correlated with acute infection VLs (n = 26). Spearman’s analysis of correlation was used to calculate the R and P values. The lines represent least-squares, best-fit linear regression. (C) Comparison of Gag-specific CD8+ T cell responses in the colonic LP 3 weeks after the last boost (n = 26). There were no detectable levels of Gag-specific IL-2+CD4+ T cell or tetramer+ CD8+ T cell responses in the adjuvant or naive groups before challenge. (D) Analysis of Ki67+CCR5+CD4+ T cell frequency in colonic IELs 3 weeks after the second boost (n = 32). The Mann-Whitney U test was used to compare the pool of the vaccinated groups with the adjuvant-only group. (E and F) The frequency of Ki67+CCR5+CD4+ T cells in colonic IELs 3 weeks after the second boost (n = 32) was positively correlated with week-2 postinfection plasma VLs, but not with the set-point VLs. Spearman’s analysis of correlation was used to calculate the R and P values. The lines represent least-squares, best-fit linear regression. Data represent mean ± SEM.