A Matter of Life or Death: Productively Infected and Bystander CD4 T Cells in Early HIV Infection.
A Matter of Life or Death: Productively Infected and Bystander CD4 T Cells in Early HIV Infection.
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DOI：
10.3389/fimmu.2020.626431
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发表时间：
2020
影响因子：
7.3
通讯作者：
Yao ZQ
中科院分区：
文献类型：
--
作者：
Cao D;Khanal S;Wang L;Li Z;Zhao J;Nguyen LN;Nguyen LNT;Dang X;Schank M;Thakuri BKC;Zhang J;Lu Z;Wu XY;Morrison ZD;El Gazzar M;Ning S;Moorman JP;Yao ZQ
初始 HIV 感染后 CD4 T 细胞死亡或存活对于病毒库和潜伏感染的发展至关重要，因此对其评估对于制定 HIV 治愈策略至关重要。在这里，我们用野生型 HIV-1 感染原代 CD4 T 细胞，并研究了早期 HIV 感染期间有效感染细胞和旁观者细胞的死亡和生存机制。我们发现，与未感染的细胞相比，HIV 感染的细胞表现出更多的程序性细胞死亡，例如细胞凋亡、细胞焦亡和铁死亡。然而，由于促凋亡/抗凋亡蛋白和信号分子的差异表达，有效感染的（p24+）细胞和旁观者（p24-）细胞表现出不同的细胞死亡模式。细胞死亡是由异常的 DNA 损伤反应 (DDR) 引发的，γH2AX 水平的增加证明了这一点，在 HIV 感染期间，γH2AX 水平与端粒长度和端粒酶水平呈负相关。从机制上讲，感染艾滋病毒的细胞在感染后表现出端粒逐渐缩短。值得注意的是，与 p24- 细胞相比，p24+ 细胞具有更长的端粒，并且端粒长度与 HIV 感染的 CD4 T 细胞中端粒酶、pAKT 和 pATM 的表达呈正相关。重要的是，阻断病毒进入减弱了 HIV 诱导的端粒酶、pAKT 和 pATM 抑制以及相关的端粒侵蚀和细胞死亡。此外，ATM 抑制促进了 HIV 感染的 CD4 T 细胞（尤其是 p24+ 细胞）的存活，并通过抑制细胞激活、HIV 感染和 DDR 来挽救端粒酶和 AKT 活性。这些结果表明，有效感染的 CD4 T 细胞和旁观者 CD4 T 细胞采用不同的生存和死亡机制，表明早期 HIV 感染期间可能存在促生存、促储存的机制。
CD4 T cell death or survival following initial HIV infection is crucial for the development of viral reservoirs and latent infection, making its evaluation critical in devising strategies for HIV cure. Here we infected primary CD4 T cells with a wild-type HIV-1 and investigated the death and survival mechanisms in productively infected and bystander cells during early HIV infection. We found that HIV-infected cells exhibited increased programmed cell death, such as apoptosis, pyroptosis, and ferroptosis, than uninfected cells. However, productively infected (p24+) cells and bystander (p24-) cells displayed different patterns of cell death due to differential expression of pro-/anti-apoptotic proteins and signaling molecules. Cell death was triggered by an aberrant DNA damage response (DDR), as evidenced by increases in γH2AX levels, which inversely correlated with telomere length and telomerase levels during HIV infection. Mechanistically, HIV-infected cells exhibited a gradual shortening of telomeres following infection. Notably, p24+ cells had longer telomeres compared to p24- cells, and telomere length positively correlated with the telomerase, pAKT, and pATM expressions in HIV-infected CD4 T cells. Importantly, blockade of viral entry attenuated the HIV-induced inhibition of telomerase, pAKT, and pATM as well as the associated telomere erosion and cell death. Moreover, ATM inhibition promoted survival of HIV-infected CD4 T cells, especially p24+ cells, and rescued telomerase and AKT activities by inhibiting cell activation, HIV infection, and DDR. These results indicate that productively infected and bystander CD4 T cells employ different mechanisms for their survival and death, suggesting a possible pro-survival, pro-reservoir mechanism during early HIV infection.