TLR3 agonist and CD40-targeting vaccination induces immune responses and reduces HIV-1 reservoirs
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
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
View: Text | PDF
Research Article AIDS/HIV

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

×

Figure 4

αCD40.HIV5pep plus poly(I:C) therapeutic vaccination rescues anti–HIV-1 T cell responses and reduces the size of HIV-1 reservoirs.

Options: View larger image (or click on image) Download as PowerPoint
αCD40.HIV5pep plus poly(I:C) therapeutic vaccination rescues anti–HIV-1 ...
Hu-mice infected with HIV-1 were treated with cART from 5 wpi to 12 wpi. The mice were vaccinated with αCD40.HIV5pep plus poly(I:C) or treated with poly(I:C) or PBS as control at 8 wpi and 11 wpi. Mice were terminated at 12 wpi. (A) Plasma HIV-1 RNA in each group at the indicated time point. (B and C) At termination, splenocytes from mice were stimulated ex vivo with corresponding 5 specific HIV-1 long peptides plus αCD28 mAb for 8 hours (BFA added at 3 hours). Representative plots (B) and summarized data (C) show percentages of IFN-γ+ and TNF-α+ CD8+ and CD4+ T cells. (D) Cell-associated HIV-1 DNA in human cells from spleen, bone marrow, and mLNs was quantified by PCR. (E) Relative levels of cell-associated HIV-1 RNA in human cells from spleens, bone marrow, and mLNs were quantified by PCR. (A and C–E) Mean ± SEM from 4 mice in each group. *P < 0.05, **P < 0.01, ***P < 0.001 by 1-way ANOVA and Bonferroni’s post hoc test.