TLR3 agonist and CD40-targeting vaccination induces immune responses and reduces HIV-1 reservoirs
TLR3 agonist and CD40-targeting vaccination induces immune responses and reduces HIV-1 reservoirs
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DOI：
10.1172/jci99005
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发表时间：
2018-10-01
影响因子：
15.9
通讯作者：
Su, Lishan
中科院分区：
文献类型：
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作者：
Cheng, Liang;Wang, Qi;Su, Lishan
HIV-1 储存库的激活和抗 HIV-1 T 细胞的诱导对于联合抗逆转录病毒治疗 (cART) 后控制 HIV-1 反弹至关重要。在这里，我们在持续感染 HIV-1 的人源化小鼠 (hu-mice) 中评估了 TLR3 激动剂和靶向 CD40 的 HIV-1 疫苗的治疗效果，该疫苗由一串 5 个高度保守的 CD4(+) 和 CD8(+) T 细胞富含表位的 HIV-1 Gag、Nef 和 Pol 区域组成，融合到重组抗人 CD40 抗体 (alpha CD40.HIV5pep) 的 C 末端。我们发现，α CD40.HIV5pep 疫苗接种与聚 (I:C) 佐剂共同施用可在 hu-小鼠中诱导 HIV-1 特异性人类 CD8(+) 和 CD4(+) T 细胞反应。有趣的是，poly(I:C) 治疗也重新激活了 HIV-1 病毒库。当在有效的 cART 治疗下对感染 HIV-1 的 hu-小鼠进行治疗时，接种聚 (I:C) 疫苗的 alpha CD40.HIV5pep 诱导了 HIV-1 特异性 CD8(+) T 细胞，并降低了淋巴组织中细胞相关的 HIV-1 DNA（或 HIV-1 储存库）水平。最引人注目的是，疫苗接种显着延迟了 cART 停止后 HIV-1 的反弹。总之，α CD40.HIV5pep 与聚 (I:C) 疫苗接种方法既激活 HIV-1 储存库的复制，又增强抗 HIV-1 T 细胞反应，导致细胞相关的 HIV-1 DNA 或储存库水平降低。我们的概念验证研究对于开发靶向 CD40 的 HIV-1 疫苗具有重要意义，该疫苗可增强抑制性 cART 患者的抗 HIV-1 免疫力并减少 HIV-1 储存。
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 (alpha CD40.HIV5pep). We show that alpha CD40.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, alpha CD40.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 alpha CD40.HIV5pep with poly(I:C) vaccination approach both activates replication of HIV-1 reservoirs and enhances the antiHIV-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.