Several mechanisms underline induction of CD4 T-cell death by human immunodeficiency virus (HIV) infection. For a long time, apoptosis was considered central to cell death involved in the depletion of CD4 T cells during HIV infection. However, which types of cell death are induced during the early phase of HIV infection in vivo remains unclear. In this study, CD4 T-cell death induced in early HIV infection was characterized using humanized mice challenged with CCR5-tropic (R5) or CXCR4-tropic (X4) HIV-1. Results showed that CD4 T-cell death was induced in the spleen 3 days post-challenge with both R5 and X4 HIV-1. Although cell death without caspase-1 and caspase-3/7 activation was preferentially observed, caspase-1⁺ pyroptosis was also significantly induced within the memory subpopulation by R5 or X4 HIV-1 and the naïve subpopulation by X4 HIV-1. In contrast, caspase-3/7⁺ apoptosis was not enhanced by either R5 or X4 HIV-1. Furthermore, phosphorylated mixed lineage kinase domain-like protein⁺ necroptosis was induced by only X4 HIV-1. These findings indicate that various types of non-apoptotic CD4 T-cell death, such as pyroptosis and necroptosis, are induced during the early phase of HIV infection in vivo.

几种机制强调了人类免疫缺陷病毒 (HIV) 感染诱导 CD4 T 细胞死亡。长期以来，细胞凋亡被认为是 HIV 感染期间 CD4 T 细胞耗竭所涉及的细胞死亡的核心。然而，在体内 HIV 感染的早期阶段诱导了哪些类型的细胞死亡仍不清楚。在这项研究中，使用 CCR5-tropic (R5) 或 CXCR4-tropic (X4) HIV-1 攻击的人源化小鼠表征了早期 HIV 感染中诱导的 CD4 T 细胞死亡。结果表明，在用 R5 和 X4 HIV-1 攻击后 3 天，脾脏中诱导了 CD4 T 细胞死亡。尽管优先观察到没有 caspase-1 和 caspase-3/7 激活的细胞死亡，但 caspase-1 ⁺R5 或 X4 HIV-1 的记忆亚群和 X4 HIV-1 的幼稚亚群也显着诱导了细胞焦亡。相比之下，R5 或 X4 HIV-1 均未增强caspase-3/7 ⁺细胞凋亡。此外，磷酸化的混合谱系激酶结构域样蛋白⁺坏死性凋亡仅由 X4 HIV-1 诱导。这些发现表明，在体内 HIV 感染的早期阶段会诱导各种类型的非凋亡 CD4 T 细胞死亡，例如细胞焦亡和坏死性凋亡。