Exacerbated AIDS Progression by PD-1 Blockade during Therapeutic Vaccination in Chronically Simian Immunodeficiency Virus-Infected Rhesus Macaques after Interruption of Antiretroviral Therapy
Exacerbated AIDS Progression by PD-1 Blockade during Therapeutic Vaccination in Chronically Simian Immunodeficiency Virus-Infected Rhesus Macaques after Interruption of Antiretroviral Therapy
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DOI：
10.1128/jvi.01785-21
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发表时间：
2022-02-01
影响因子：
5.4
通讯作者：
Sun, Caijun
中科院分区：
文献类型：
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作者：
Wu, Chunxiu;He, Yizi;Sun, Caijun
HIV-1潜伏感染细胞的持续存在是HIV-1根除的主要障碍，HIV-1感染过程中免疫抑制通路的激活和CD 8（+）T细胞功能障碍可能加剧潜伏感染细胞的形成和维持。我们先前的研究结果表明，预防性疫苗接种与PD-1阻断相结合产生了不同的免疫应答特征，并有效控制了恒河猴中的高致病性SIVmac 239感染。然而，令我们惊讶的是，我们在本文中发现，治疗性疫苗接种与PD-1阻断的组合导致病毒储库的活化、治疗中断后更快的病毒反弹、加速AIDS进展，并且最终导致慢性SIV感染的猕猴在抗逆转录病毒疗法（ART）中断后死亡。我们的研究进一步证明，SIV前病毒优先富集在PD-1（+）CD 4（+）T细胞中，这是由于它们对病毒进入的易感性、强大的增殖能力和不能进行病毒转录。此外，在PD-1阻断后，病毒潜伏期被有效地重新激活。总之，这些结果表明，PD-1阻断可能是一把双刃剑的HIV-1免疫治疗，并提供了重要的洞察力对合理设计的免疫治疗策略的HIV-1 cure.IMPORTANCE因为它是最具挑战性的公共卫生问题之一，有没有临床有效的治疗策略对HIV-1感染。我们证明了预防性疫苗接种与PD-1阻断相结合产生了不同的免疫应答特征，并在恒河猴中更好地控制了高致病性SIVmac 239感染。在本研究中，令我们惊讶的是，治疗性疫苗接种期间的PD-1阻断加速了ART中断后慢性SIV感染猕猴中潜伏储库的重新激活和AIDS进展。我们的研究进一步证明，潜伏的SIV前病毒优先富集在PD-1（+）CD 4（+）T细胞中，因为其对病毒进入的敏感性，抑制SIV转录，并具有强大的增殖能力，并且PD-1阻断可有效地重新激活病毒潜伏期。因此，PD-1阻断剂可能是艾滋病治疗的一把双刃剑。这些发现引起了人们对进一步探索针对HIV-1感染和其他新兴传染病的新疗法的兴趣。
The persistence of cells latently infected with HIV-1, named the latent reservoir, is the major barrier to HIV-1 eradication, and the formation and maintenance of the latent reservoir might be exacerbated by activation of the immunoinhibitory pathway and dysfunction of CD8(+) T cells during HIV-1 infection. Our previous findings demonstrated that prophylactic vaccination combined with PD-1 blockade generated distinct immune response profiles and conferred effective control of highly pathogenic SIVmac239 infection in rhesus macaques. However, to our surprise, herein we found that a therapeutic vaccination in combination with PD-1 blockade resulted in activation of the viral reservoir, faster viral rebound after treatment interruption, accelerated AIDS progression, and, ultimately, death in chronically SIV-infected macaques after antiretroviral therapy (ART) interruption. Our study further demonstrated that the SIV provirus was preferentially enriched in PD-1(+)CD4(+) T cells due to their susceptibility to viral entry, potent proliferative ability, and inability to perform viral transcription. In addition, the viral latency was effectively reactivated upon PD-1 blockade. Together, these results suggest that PD-1 blockade may be a double-edged sword for HIV-1 immunotherapy and provide important insight toward the rational design of immunotherapy strategies for an HIV-1 cure.IMPORTANCE As it is one of the most challenging public health problems, there are no clinically effective cure strategies against HIV-1 infection. We demonstrated that prophylactic vaccination combined with PD-1 blockade generated distinct immune response profiles and conferred better control of highly pathogenic SIVmac239 infection in rhesus macaques. In the present study, to our surprise, PD-1 blockade during therapeutic vaccination accelerated the reactivation of latent reservoir and AIDS progression in chronically SIV-infected macaques after ART interruption. Our study further demonstrated that the latent SIV provirus was preferentially enriched in PD-1(+)CD4(+) T cells because of its susceptibility to viral entry, inhibition of SIV transcription, and potent ability of proliferation, and the viral latency was effectively reactivated by PD-1 blockade. Therefore, PD-1 blockade might be a double-edged sword for AIDS therapy. These findings provoke interest in further exploring novel treatments against HIV-1 infection and other emerging infectious diseases.