Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
"Romeo ed Enrica Invernizzi," Istituto Nazionale di Genetica Molecolare (INGM), Milan 20122, Italy.
Proc Natl Acad Sci U S A. 2018 Oct 9;115(41):E9659-E9667. doi: 10.1073/pnas.1806695115. Epub 2018 Sep 26.
HIV integrates into the host genome to create a persistent viral reservoir. Stimulation of CD4 memory T lymphocytes with common γc-chain cytokines renders these cells more susceptible to HIV infection, making them a key component of the reservoir itself. IL-15 is up-regulated during primary HIV infection, a time when the HIV reservoir established. Therefore, we investigated the molecular and cellular impact of IL-15 on CD4 T-cell infection. We found that IL-15 stimulation induces SAM domain and HD domain-containing protein 1 (SAMHD1) phosphorylation due to cell cycle entry, relieving an early block to infection. Perturbation of the pathways downstream of IL-15 receptor (IL-15R) indicated that SAMHD1 phosphorylation after IL-15 stimulation is JAK dependent. Treating CD4 T cells with Ruxolitinib, an inhibitor of JAK1 and JAK2, effectively blocked IL-15-induced SAMHD1 phosphorylation and protected CD4 T cells from HIV infection. Using high-resolution single-cell immune profiling using mass cytometry by TOF (CyTOF), we found that IL-15 stimulation altered the composition of CD4 T-cell memory populations by increasing proliferation of memory CD4 T cells, including CD4 T memory stem cells (T). IL-15-stimulated CD4 T, harboring phosphorylated SAMHD1, were preferentially infected. We propose that IL-15 plays a pivotal role in creating a self-renewing, persistent HIV reservoir by facilitating infection of CD4 T cells with stem cell-like properties. Time-limited interventions with JAK1 inhibitors, such as Ruxolitinib, should prevent the inactivation of the endogenous restriction factor SAMHD1 and protect this long-lived CD4 T-memory cell population from HIV infection.
HIV 整合到宿主基因组中以创建一个持久的病毒储存库。用共同的 γc 链细胞因子刺激 CD4 记忆 T 淋巴细胞，使这些细胞更容易感染 HIV，使它们成为储存库本身的关键组成部分。IL-15 在原发性 HIV 感染期间上调，此时 HIV 储存库建立。因此，我们研究了 IL-15 对 CD4 T 细胞感染的分子和细胞影响。我们发现，IL-15 刺激通过细胞周期进入诱导 SAM 结构域和 HD 结构域包含蛋白 1（SAMHD1）磷酸化，从而缓解感染的早期阻断。干扰 IL-15 受体（IL-15R）下游途径表明，IL-15 刺激后的 SAMHD1 磷酸化是 JAK 依赖性的。用 JAK1 和 JAK2 的抑制剂鲁索利替尼处理 CD4 T 细胞，可有效阻断 IL-15 诱导的 SAMHD1 磷酸化，并保护 CD4 T 细胞免受 HIV 感染。使用高分辨率单细胞免疫分析，使用飞行时间（CyTOF）的质谱细胞术，我们发现，IL-15 刺激通过增加记忆 CD4 T 细胞的增殖，包括 CD4 T 记忆干细胞（T），改变 CD4 T 细胞记忆群体的组成。IL-15 刺激的 CD4 T 细胞，含有磷酸化的 SAMHD1，优先被感染。我们提出，IL-15 通过促进具有干细胞样特性的 CD4 T 细胞的感染，在创建自我更新、持久的 HIV 储存库中发挥关键作用。用 JAK1 抑制剂，如鲁索利替尼进行限时干预，应防止内源性限制因子 SAMHD1 的失活，并保护这种长寿的 CD4 T 记忆细胞群体免受 HIV 感染。
