期刊
JOURNAL OF VIROLOGY
卷 96, 期 3, 页码 -出版社
AMER SOC MICROBIOLOGY
关键词
rhesus macaques; HIV; SIV; latent viral reservoir; programmed cell death protein 1 (PD-1) blockade; therapeutic vaccination
类别
资金
- National Natural Science Foundation of China [81971927, 32000124]
- National Science and Technology Major Project of China [2018ZX10731101-002]
- Science and Technology Planning Project of Shenzhen City [20190804095916056, JCYJ20200109142601702, JSGG20200225152008136]
- Natural Science Foundation of Guangdong Province [2019A1515110458, 2021A1515010456]
- Municipal Health and Medical Cooperation Innovation Major Project of Guangzhou City [201704020219, 201803040002]
- China Postdoctoral Science Foundation [2019M663140, 2020T130150ZX]
The persistence of latently infected cells is a major barrier to HIV-1 eradication, and PD-1 blockade can exacerbate the formation and maintenance of the latent reservoir. However, our study found that PD-1 blockade during therapeutic vaccination resulted in activation of the viral reservoir, rapid viral rebound, accelerated AIDS progression, and death in chronically SIV-infected macaques after treatment interruption.
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.
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