Department of Infectious Diseases, Virology, University of Heidelberg, Heidelberg, Germany.
Nat Med. 2012 Nov;18(11):1682-7. doi: 10.1038/nm.2964.
Unlike activated CD4(+) T cells, resting CD4(+) T cells are highly resistant to productive HIV-1 infection. Early after HIV-1 entry, a major block limits reverse transcription of incoming viral genomes. Here we show that the deoxynucleoside triphosphate triphosphohydrolase SAMHD1 prevents reverse transcription of HIV-1 RNA in resting CD4(+) T cells. SAMHD1 is abundantly expressed in resting CD4(+) T cells circulating in peripheral blood and residing in lymphoid organs. The early restriction to infection in unstimulated CD4(+) T cells is overcome by HIV-1 or HIV-2 virions into which viral Vpx is artificially or naturally packaged, respectively, or by addition of exogenous deoxynucleosides. Vpx-mediated proteasomal degradation of SAMHD1 and elevation of intracellular deoxynucleotide pools precede successful infection by Vpx-carrying HIV. Resting CD4(+) T cells from healthy donors following SAMHD1 silencing or from a patient with Aicardi-Goutières syndrome homozygous for a nonsense mutation in SAMHD1 were permissive for HIV-1 infection. Thus, SAMHD1 imposes an effective restriction to HIV-1 infection in the large pool of noncycling CD4(+) T cells in vivo. Bypassing SAMHD1 was insufficient for the release of viral progeny, implicating other barriers at later stages of HIV replication. Together, these findings may unveil new ways to interfere with the immune evasion and T cell immunopathology of pandemic HIV-1.
与激活的 CD4(+) T 细胞不同，静止的 CD4(+) T 细胞对 HIV-1 的有效感染具有很强的抵抗力。HIV-1 进入后早期，一个主要的阻断限制了进入病毒基因组的逆转录。在这里，我们表明脱氧核苷三磷酸三磷酸水解酶 SAMHD1 可防止静止的 CD4(+) T 细胞中 HIV-1 RNA 的逆转录。SAMHD1 在循环于外周血中的静止的 CD4(+) T 细胞和驻留在淋巴器官中的静止的 CD4(+) T 细胞中大量表达。未受刺激的 CD4(+) T 细胞中早期的感染限制被 HIV-1 或 HIV-2 病毒粒子克服，分别通过人工或自然包装病毒 Vpx 或通过添加外源性脱氧核苷。Vpx 介导的 SAMHD1 蛋白酶体降解和细胞内脱氧核苷酸池的升高先于成功感染带有 Vpx 的 HIV。沉默 SAMHD1 的健康供体的静止 CD4(+) T 细胞或携带 SAMHD1 无意义突变的 Aicardi-Goutières 综合征患者的静止 CD4(+) T 细胞对 HIV-1 感染具有易感性。因此，SAMHD1 在体内大量非循环 CD4(+) T 细胞中对 HIV-1 感染施加了有效的限制。绕过 SAMHD1 不足以释放病毒后代，这表明 HIV 复制的后期阶段存在其他障碍。总之，这些发现可能揭示了干扰大流行 HIV-1 的免疫逃避和 T 细胞免疫病理学的新方法。
