TLR3 agonist and CD40-targeting vaccination induces immune responses and reduces HIV-1 reservoirs
Liang Cheng, … , Yves Levy, Lishan Su
Liang Cheng, … , Yves Levy, Lishan Su
Published October 1, 2018; First published August 27, 2018
Citation Information: J Clin Invest. 2018;128(10):4387-4396. https://doi.org/10.1172/JCI99005.
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Categories: Research Article AIDS/HIV Vaccines

TLR3 agonist and CD40-targeting vaccination induces immune responses and reduces HIV-1 reservoirs

Abstract

Activation of HIV-1 reservoirs and induction of anti–HIV-1 T cells are critical to control HIV-1 rebound after combined antiretroviral therapy (cART). Here we evaluated in humanized mice (hu-mice) with persistent HIV-1 infection the therapeutic effect of TLR3 agonist and a CD40-targeting HIV-1 vaccine, which consists of a string of 5 highly conserved CD4+ and CD8+ T cell epitope-rich regions of HIV-1 Gag, Nef, and Pol fused to the C-terminus of a recombinant anti-human CD40 antibody (αCD40.HIV5pep). We show that αCD40.HIV5pep vaccination coadministered with poly(I:C) adjuvant induced HIV-1–specific human CD8+ and CD4+ T cell responses in hu-mice. Interestingly, poly(I:C) treatment also reactivated HIV-1 reservoirs. When administrated in therapeutic settings in HIV-1–infected hu-mice under effective cART, αCD40.HIV5pep with poly(I:C) vaccination induced HIV-1–specific CD8+ T cells and reduced the level of cell-associated HIV-1 DNA (or HIV-1 reservoirs) in lymphoid tissues. Most strikingly, the vaccination significantly delayed HIV-1 rebound after cART cessation. In summary, the αCD40.HIV5pep with poly(I:C) vaccination approach both activates replication of HIV-1 reservoirs and enhances the anti–HIV-1 T cell response, leading to a reduced level of cell-associated HIV-1 DNA or reservoirs. Our proof-of-concept study has significant implication for the development of CD40-targeting HIV-1 vaccine to enhance anti–HIV-1 immunity and reduce HIV-1 reservoirs in patients with suppressive cART.

Authors

Liang Cheng, Qi Wang, Guangming Li, Riddhima Banga, Jianping Ma, Haisheng Yu, Fumihiko Yasui, Zheng Zhang, Giuseppe Pantaleo, Matthieu Perreau, Sandra Zurawski, Gerard Zurawski, Yves Levy, Lishan Su

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Figure 3

Poly(I:C) treatment reactivates HIV-1 production in cART-treated HIV-1–infected individuals.

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Poly(I:C) treatment reactivates HIV-1 production in cART-treated HIV-1–i...
(A–D) Resting memory CD4+ T cells (HLA-DR–CD25–CD69–) of 3 aviremic ART-treated HIV-1–infected individuals were used for virus outgrowth assay. (A) Proportion of HIV-1 RNA-positive wells induced following poly(I:C) treatment. Wells with detectable HIV-1 RNA (≥200 HIV-1 RNA copies/ml) were referred to as HIV-1 RNA-positive wells for the condition tested. (B) Levels of HIV-1 RNA copies/ml induced following poly(I:C) treatment. (C) Frequencies of cells containing inducible replication-competent virus as measured by RUPM induced upon poly(I:C) treatment. (D) Fraction of poly(I:C)-induced cells containing replication-competent virus as assessed by HIV-1 RNA as compared with anti-CD3/28. Panels A–B were generated using the 5 replicates of the highest concentration of cells (5 × 105 cells) of all conditions by VOA in 3 aviremic cART-treated HIV-1–infected individuals, except the conditions with poly(I:C) at 10 μg/ml, which were generated using 2 aviremic ART-treated HIV-1–infected individuals. Subjects were color-coded and each color corresponds to a subject (B and C). Histograms correspond to mean (C and D) and red bars correspond to SEM (B–D). Red asterisks indicate statistical significance as compared with the unstimulated or unexposed condition (*P < 0.05). Anti-CD3/anti-CD28 MAb is represented by 3/28. Statistical significance was obtained using either 2-tailed Chi-square analysis for comparison of positive proportions (A) or 1-way ANOVA (Kruskal-Wallis test) followed by Wilcoxon matched-pairs 2-tailed signed rank test (B–D). (E and F) Combined cells from spleen, bone marrow, and mLN of cART–treated HIV-1–infected hu-mice were cultured ex vivo with poly(I:C) (5 μg/ml), R848(5 μg/ml), R837(5 μg/ml), CpG-B (5 μg/ml), and SAHA (1 μM) in the presence of the antiretroviral drug nevirapine. Each dot represents data from 1 mouse. Relative cell-associated HIV-1 RNA (E) and DNA (F) were detected 48 hours after culture. **P < 0.01, ***P < 0.001 by unpaired, 2-tailed Student’s t test.