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恒河猴巨细胞病毒特异性 CD8 细胞毒性 T 淋巴细胞在慢性 SIVmac239 感染中不会发生功能衰竭。

Rhesus Cytomegalovirus-Specific CD8 Cytotoxic T Lymphocytes Do Not Become Functionally Exhausted in Chronic SIVmac239 Infection.

机构信息

Medical Scientist Training Program, University of Miami Miller School of Medicine, Miami, FL, United States.

Department of Pathology, University of Miami Miller School of Medicine, Miami, FL, United States.

出版信息

Front Immunol. 2020 Aug 12;11:1960. doi: 10.3389/fimmu.2020.01960. eCollection 2020.

Abstract

CD8 cytotoxic T lymphocytes (CTLs) exert potent antiviral activity after HIV/SIV infection. However, efforts to harness the antiviral efficacy of CTLs for HIV/SIV prophylaxis and therapy have been severely hindered by two major problems: viral escape and exhaustion. By contrast, CTLs directed against human cytomegalovirus (HCMV), a ubiquitous chronic herpesvirus, seldom select for escape mutations and remain functional and refractory to exhaustion during chronic HCMV and HIV infection. Recently, attempts have been made to retarget HCMV-specific CTLs for cancer immunotherapy. We speculate that such a strategy may also be beneficial in the context of HIV/SIV infection, facilitating CTL-mediated control of HIV/SIV replication. As a preliminary assessment of the validity of this approach, we investigated the phenotypes and functionality of rhesus CMV (RhCMV)-specific CTLs in SIVmac239-infected Indian rhesus macaques (RMs), a crucial HIV animal model system. We recently identified two immunodominant, -restricted CTL epitopes derived from RhCMV proteins and sought to evaluate the phenotypic and functional characteristics of these CTL populations in chronic SIVmac239 infection. We analyzed and directly compared RhCMV- and SIVmac239-specific CTLs during SIVmac239 infection in a cohort of and RMs. CTL populations specific for at least one of the RhCMV-derived CTL epitopes were detected in ten of eleven animals tested, and both populations were detected in five of these animals. Neither RhCMV-specific CTL population exhibited significant changes in frequency, memory phenotype, granzyme B expression, exhaustion marker (PD-1 and CTLA-4) expression, or polyfunctionality between pre- and chronic SIVmac239 infection timepoints. In chronic SIVmac239 infection, RhCMV-specific CTLs exhibited higher levels of granzyme B expression and polyfunctionality, and lower levels of exhaustion marker expression, than SIVmac239-specific CTLs. Additionally, compared to SIVmac239-specific CTLs, greater proportions of RhCMV-specific CTLs were of the terminally differentiated effector memory phenotype (CD28 CCR7) during chronic SIVmac239 infection. These results suggest that, in contrast to SIVmac239-specific CTLs, RhCMV-specific CTLs maintain their phenotypes and cytolytic effector functions during chronic SIVmac239 infection, and that retargeting RhCMV-specific CTLs might be a promising SIV immunotherapeutic strategy.

摘要

CD8 细胞毒性 T 淋巴细胞(CTLs)在感染 HIV/SIV 后发挥强大的抗病毒活性。然而,利用 CTLs 预防和治疗 HIV/SIV 的抗病毒功效的努力受到两个主要问题的严重阻碍:病毒逃逸和衰竭。相比之下,针对人类巨细胞病毒(HCMV)的 CTLs 很少选择逃逸突变,并且在慢性 HCMV 和 HIV 感染期间保持功能和对衰竭有抗性。最近,人们尝试将 HCMV 特异性 CTLs 重新靶向用于癌症免疫治疗。我们推测,在 HIV/SIV 感染的情况下,这种策略也可能是有益的,有助于 CTL 介导的 HIV/SIV 复制控制。作为对这种方法有效性的初步评估,我们研究了 SIVmac239 感染的印度恒河猴(RMs)中针对恒河猴巨细胞病毒(RhCMV)的 CTLs 的表型和功能。我们最近鉴定了两个免疫优势的、受限制的 CTL 表位,来自 RhCMV 蛋白,并试图评估这些 CTL 群体在慢性 SIVmac239 感染中的表型和功能特征。我们在一组 和 只 RMs 中分析并直接比较了 RhCMV 和 SIVmac239 特异性 CTLs 在 SIVmac239 感染期间的情况。在 11 只接受测试的动物中,有 10 只检测到至少一种 RhCMV 衍生的 CTL 表位特异性 CTL 群体,而这 5 只动物均检测到这两种群体。在 SIVmac239 感染的前和慢性感染时间点之间,既没有 RhCMV 特异性 CTL 群体在频率、记忆表型、颗粒酶 B 表达、衰竭标志物(PD-1 和 CTLA-4 表达)或多效性方面发生显著变化。在慢性 SIVmac239 感染中,与 SIVmac239 特异性 CTLs 相比,RhCMV 特异性 CTLs 表现出更高水平的颗粒酶 B 表达和多效性,以及更低水平的衰竭标志物表达。此外,与 SIVmac239 特异性 CTLs 相比,在慢性 SIVmac239 感染期间,RhCMV 特异性 CTLs 中更多比例是终末分化的效应记忆表型(CD28 CCR7)。这些结果表明,与 SIVmac239 特异性 CTLs 相比,RhCMV 特异性 CTLs 在慢性 SIVmac239 感染期间保持其表型和细胞毒性效应功能,并且重定向 RhCMV 特异性 CTLs 可能是一种有前途的 SIV 免疫治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0db7/7457070/9bcaa5ddea0e/fimmu-11-01960-g001.jpg

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