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. 2011 Dec 9;30(1):59-68.
doi: 10.1016/j.vaccine.2011.10.043. Epub 2011 Oct 29.

TLR agonists and/or IL-15 adjuvanted mucosal SIV vaccine reduced gut CD4⁺ memory T cell loss in SIVmac251-challenged rhesus macaques

Yongjun Sui  1 , Susan Gagnon, Amiran Dzutsev, Qing Zhu, Huifeng Yu, Alison Hogg, Yichuan Wang, Zheng Xia, Igor M Belyakov, David Venzon, Dennis Klinman, Warren Strober, Brian Kelsall, Genoveffa Franchini, Jay A Berzofsky
Affiliations

TLR agonists and/or IL-15 adjuvanted mucosal SIV vaccine reduced gut CD4⁺ memory T cell loss in SIVmac251-challenged rhesus macaques

Yongjun Sui et al. Vaccine. .

Abstract

Adjuvant plays an important role in increasing and directing vaccine-induced immune responses. In a previous study, we found that a mucosal SIV vaccine using a combination of IL-15 and TLR agonists as adjuvant mediated partial protection against SIVmac251 rectal challenge, whereas neither IL-15 nor TLR agonists alone as an adjuvant impacted the plasma viral loads. In this study, dissociation of CD4(+) T cell preservation with viral loads was observed in the animals vaccinated with adjuvants. Significantly higher levels of memory CD4(+) T cell numbers were preserved after SIVmac251 infection in the colons of the animals vaccinated with vaccine containing any of these adjuvants compared to no adjuvant. When we measured the viral-specific CD8(+) tetramer responses in the colon lamina propria, we found significantly higher levels of gag, tat, and pol epitope tetramer(+) T cell responses in these animals compared to ones without adjuvant, even if some of the animals had similarly high viral loads. Furthermore, this CD4(+) T preservation was positively correlated with increased levels of gag and Tat, but not pol tetramer(+) T cell responses, and inversely correlated with beta-chemokine expression. The pre-challenged APOBEC3G expression level, which has previously been shown inversely associated with viral loads, was further found positively correlated with CD4(+) T cell number preservation. Overall, these data highlight one unrecognized role of adjuvant in HIV vaccine development, and show that vaccines can produce a surprising discordance between CD4(+) T cell levels and SIV viral load.

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Figures

Figure 1
Figure 1. CD4+ memory T cell numbers were preserved after SIV infection in the colons of the macaques immunized with vaccines containing adjuvants
(A). Post/pre CD4+ T cell ratios were measured in the colon lamina propria after and before SIV challenge. (B, C). CD4+ central and transitional memory T lymphocyte (TCM &Trm: CD28+CD95+CD4+ T cell percentage within the total lymphocyte gate) and effector memory T lymphocyte (TEM: CD28-CD95+ CD4+ T cell percentage within the total lymphocyte gate) responses were measured in the colon lamina propria 6 months post SIV infection. Comparisons among the groups were performed by two-tailed Mann Whitney tests. (D-F). Correlations between colon VL and post/pre CD4+ T cell ratios (6 months post infection and before infection), TCM &Trm and TEM (both 6 months post infection) were evaluated by a two-tailed Spearman's rank test. The animals in different groups were color-coded: Vac+TLRLs in red, Vac+IL-15 in blue, Vac+TLRLs+IL-15 in green, Vac-only in orange, and TLRLs+IL-15-adjuvant-only in purple. Data show mean and S.E.M.
Figure 2
Figure 2. Pre-challenge A3G expression level correlated with CD4+ T memory cell number preservation
Correlations between pre-challenge A3G expression level in MLN and post/pre CD4+ T cell ratios (A, 6 months post infection and before infection); TCM &Trm and TEM (B, C, both 6 months post infection) in the colons were evaluated by a two-tailed Spearman's rank test. The animals in different groups were color-coded: Vac+TLRLs in red, Vac+IL-15 in blue, Vac+TLRLs+IL-15 in green, Vac-only in orange, and TLRLs+IL-15-adjuvant-only in purple.
Figure 3
Figure 3. Serum β-chemokines did not contribute to CD4+ T memory cell preservation
Serum MIP-1β (A) and RANTES (B) expression levels of the macaques 6 months post-infection were measured. Correlations between serum MIP-1β / RANTES expression levels and TCM &Trm in the colon (C, D), and colon VL (E, F) were evaluated by a two-tailed Spearman's rank test. The animals in different groups were color-coded: Vac+TLRLs in red, Vac+IL-15 in blue, Vac+TLRLs+IL-15 in green, Vac-only in orange, and TLRLs+IL-15-adjuvant-only in purple. Data show mean and S.E.M.
Figure 4
Figure 4. Virus specific tetramer+CD8+ T cell responses in the colon lamina propria of the macaques 6 months post-infection
(A). Gating strategies of virus specific tetramer+CD8+ T cells. (B). 6 virus specific Mamu A*01 tetramer responses were measured in the colon lamina propria of the macaques 6 months post-infection. The sum of these 6 tetramer responses was also shown. Comparisons among the groups were performed by two-tailed Mann Whitney tests. Data show mean and S.E.M.
Figure 5
Figure 5. Correlations between CD4+ memory T cell ratios / numbers and virus specific tetramer+CD8+ T cell responses in the colons of the macaques post SIVmac251 infection
Correlations between CD4+ memory T cell ratios / numbers and virus specific tetramer+CD8+ T cell responses in the colons of the macaques post SIVmac251 infection were evaluated by a two-tailed Spearman's rank test. The animals in different groups were color-coded: Vac+TLRLs in red, Vac+IL-15 in blue, Vac+TLRLs+IL-15 in green, Vac-only in orange, and TLRLs+IL-15-adjuvant-only in purple.
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