Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006, USA; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA.
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA.
EBioMedicine. 2022 Oct;84:104253. doi: 10.1016/j.ebiom.2022.104253. Epub 2022 Sep 8.
Harnessing CD8 T cell responses is being explored to achieve HIV remission. Although HIV-specific CD8 T cells become dysfunctional without treatment, antiretroviral therapy (ART) partially restores their function. However, the extent of this recovery under long-term ART is less understood.
We analyzed the differentiation status and function of HIV-specific CD8 T cells after long-term ART initiated in acute or chronic HIV infection ex vivo and upon in vitro recall.
ART initiation in any stage of acute HIV infection promoted the persistence of long-lived HIV-specific CD8 T cells with high expansion (P<0·0008) and cytotoxic capacity (P=0·02) after in vitro recall, albeit at low cell number (P=0·003). This superior expansion capacity correlated with stemness (r=0·90, P=0·006), measured by TCF-1 expression, similar to functional HIV-specific CD8 T cells found in spontaneous controllers. Importanly, TCF-1 expression in these cells was associated with longer time to viral rebound ranging from 13 to 48 days after ART interruption (r =0·71, P=0·03). In contrast, ART initiation in chronic HIV infection led to more differentiated HIV-specific CD8 T cells lacking stemness properties and exhibiting residual dysfunction upon recall, with reduced proliferation and cytolytic activity.
ART initiation in acute HIV infection preserves functional HIV-specific CD8 T cells, albeit at numbers too low to control viral rebound post-ART. HIV remission strategies may need to boost HIV-specific CD8 T cell numbers and induce stem cell-like properties to reverse the residual dysfunction persisting on ART in people treated after acute infection prior to ART release.
U.S. National Institutes of Health and U.S. Department of Defense.
人们正在探索利用 CD8 T 细胞应答来实现 HIV 缓解。虽然未经治疗时 HIV 特异性 CD8 T 细胞会出现功能障碍，但抗逆转录病毒疗法（ART）可部分恢复其功能。然而，在长期接受 ART 治疗的情况下，这种恢复的程度了解较少。
我们分析了急性或慢性 HIV 感染患者在开始接受长期 ART 治疗后，体外和体外回忆时 HIV 特异性 CD8 T 细胞的分化状态和功能。
在急性 HIV 感染的任何阶段开始 ART 治疗，均可促进长寿的 HIV 特异性 CD8 T 细胞的持续存在，这些细胞具有高扩增（P<0·0008）和细胞毒性能力（P=0·02），尽管细胞数量较少（P=0·003）。这种优越的扩增能力与干性相关（r=0·90，P=0·006），通过 TCF-1 表达来衡量，类似于在自发性控制者中发现的功能性 HIV 特异性 CD8 T 细胞。重要的是，这些细胞中的 TCF-1 表达与病毒反弹后的时间有关，范围从 ART 中断后 13 至 48 天（r =0·71，P=0·03）。相比之下，在慢性 HIV 感染中开始 ART 治疗会导致更分化的 HIV 特异性 CD8 T 细胞，缺乏干性特征，并且在回忆时表现出残留的功能障碍，增殖和细胞毒性活性降低。
在急性 HIV 感染中开始 ART 治疗可保留功能性 HIV 特异性 CD8 T 细胞，尽管数量太少，无法在 ART 后控制病毒反弹。在 ART 释放之前，治疗急性感染后开始接受 ART 的患者，HIV 缓解策略可能需要增加 HIV 特异性 CD8 T 细胞数量并诱导干细胞样特性，以逆转持续存在的残留功能障碍。
美国国立卫生研究院和美国国防部。
