Gladstone Institute of Virology and Immunology, University of California, San Francisco, San Francisco, California, USA.
Gladstone Institute of Virology and Immunology, University of California, San Francisco, San Francisco, California, USA
J Virol. 2019 Nov 26;93(24). doi: 10.1128/JVI.00666-19. Print 2019 Dec 15.
Human immunodeficiency virus type 2 (HIV-2) infection results in a milder course of disease and slower progression to AIDS than does HIV-1. We hypothesized that this difference may be due to degradation of the sterile alpha motif and HD domain 1 (SAMHD1) host restriction factor by the HIV-2 Vpx gene product, thereby diminishing abortive infection and pyroptotic cell death within bystander CD4 T cells. We have compared CD4 T cell death in tonsil-derived human lymphoid aggregate cultures (HLACs) infected with wild-type HIV-2, HIV-2 ΔVpx, or HIV-1. In contrast to our hypothesis, HIV-2, HIV-2 ΔVpx, and HIV-1 induced similar levels of bystander CD4 T cell death. In all cases, cell death was blocked by AMD3100, a CXCR4 entry inhibitor, but not by raltegravir, an integrase, indicating that only early life cycle events were required. Cell death was also blocked by a caspase-1 inhibitor, a key enzyme promoting pyroptosis, but not by a caspase-3 inhibitor, an important enzyme in apoptosis. HIV-1-induced abortive infection and pyroptotic cell death were also not reduced by forced encapsidation of HIV-2 Vpx into HIV-1 virions. Together, these findings indicate that HIV-2 and HIV-1 support similar levels of CD4 T cell depletion despite HIV-2 Vpx-mediated degradation of the SAMHD1 transcription factor. The milder disease course observed with HIV-2 infection likely stems from factors other than abortive infection and caspase-1-dependent pyroptosis in bystander CD4 T cells. CD4 T cell depletion during HIV-1 infection involves the demise of bystander CD4 T cells due to abortive infection, viral DNA sensing, inflammasome assembly, and death by caspase-1-dependent pyroptosis. HIV-2 infection is associated with milder disease and lower rates of CD4 T cell loss. We hypothesized that HIV-2 infection produces lower levels of pyroptosis due to the action of its Vpx gene product. Vpx degrades the SAMHD1 restriction factor, potentially reducing abortive forms of infection. However, in tonsil cell cultures, HIV-2, HIV-2 ΔVpx, and HIV-1 induced indistinguishable levels of pyroptosis. Forced encapsidation of Vpx into HIV-1 virions also did not reduce pyroptosis. Thus, SAMHD1 does not appear to play a key role in the induction of bystander cell pyroptosis. Additionally, the milder clinical course of HIV-2-induced disease is apparently not explained by a decrease in this inflammatory form of programmed cell death.
人类免疫缺陷病毒 2 型（HIV-2）感染导致疾病进程较 HIV-1 更为轻微，向艾滋病的进展速度也较慢。我们假设这种差异可能是由于 HIV-2 的 Vpx 基因产物降解了无活性的α基序和 HD 结构域 1（SAMHD1）宿主限制因子，从而减少了旁观者 CD4 T 细胞中的无效感染和细胞焦亡。我们比较了野生型 HIV-2、HIV-2 ΔVpx 和 HIV-1 感染扁桃体衍生的人类淋巴样聚集培养物（HLAC）中 CD4 T 细胞死亡的情况。与我们的假设相反，HIV-2、HIV-2 ΔVpx 和 HIV-1 诱导的旁观者 CD4 T 细胞死亡水平相似。在所有情况下，CXCR4 进入抑制剂 AMD3100 阻断了细胞死亡，但整合酶抑制剂 raltegravir 没有阻断，这表明仅需要早期生命周期事件。细胞死亡也被 caspase-1 抑制剂阻断，caspase-1 是促进细胞焦亡的关键酶，但 caspase-3 抑制剂没有阻断，caspase-3 是细胞凋亡中的重要酶。强制将 HIV-2 的 Vpx 包裹到 HIV-1 病毒粒子中也不会减少 HIV-1 诱导的无效感染和细胞焦亡。综上所述，这些发现表明，尽管 HIV-2 的 Vpx 介导了 SAMHD1 转录因子的降解，但 HIV-2 和 HIV-1 支持相似水平的 CD4 T 细胞耗竭。与 HIV-2 感染相关的较轻的疾病病程可能源自旁观者 CD4 T 细胞中无效感染和 caspase-1 依赖性细胞焦亡以外的因素。HIV-1 感染导致 CD4 T 细胞耗竭，涉及旁观者 CD4 T 细胞因无效感染、病毒 DNA 感应、炎性小体组装和 caspase-1 依赖性细胞焦亡而死亡。HIV-2 感染与疾病较轻和 CD4 T 细胞丢失率较低有关。我们假设 HIV-2 感染由于其 Vpx 基因产物的作用而产生较低水平的细胞焦亡。Vpx 降解了 SAMHD1 限制因子，可能减少了无效形式的感染。然而，在扁桃体细胞培养物中，HIV-2、HIV-2 ΔVpx 和 HIV-1 诱导的细胞焦亡水平无法区分。强制将 Vpx 包裹到 HIV-1 病毒粒子中也不会减少细胞焦亡。因此，SAMHD1 似乎在诱导旁观者细胞焦亡中没有发挥关键作用。此外，HIV-2 诱导疾病的较轻临床病程显然不能用这种炎症形式的程序性细胞死亡减少来解释。
