Department Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, USA.
Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
Virology. 2014 Apr;454-455:60-6. doi: 10.1016/j.virol.2014.02.006. Epub 2014 Feb 22.
Previously, we showed that ADAM10 is necessary for HIV-1 replication in primary human macrophages and immortalized cell lines. Silencing ADAM10 expression interrupted the HIV-1 life cycle prior to nuclear translocation of viral cDNA. Furthermore, our data indicated that HIV-1 replication depends on the expression of ADAM15 and γ-secretase, which proteolytically processes ADAM10. Silencing ADAM15 or γ-secretase expression inhibits HIV-1 replication between reverse transcription and nuclear entry. Here, we show that ADAM10 expression also supports replication in CD4(+) T lymphocytes. The intracellular domain (ICD) of ADAM10 associates with the HIV-1 pre-integration complex (PIC) in the cytoplasm and immunoprecipitates and co-localizes with HIV-1 integrase, a key component of PIC. Taken together, our data support a model whereby ADAM15/γ-secretase processing of ADAM10 releases the ICD, which then incorporates into HIV-1 PIC to facilitate nuclear trafficking. Thus, these studies suggest ADAM10 as a novel therapeutic target for inhibiting HIV-1 prior to nuclear entry.
先前，我们表明 ADAM10 对于原发性人巨噬细胞和永生化细胞系中的 HIV-1 复制是必要的。沉默 ADAM10 的表达会在病毒 cDNA 核转位之前中断 HIV-1 生命周期。此外，我们的数据表明 HIV-1 复制依赖于 ADAM15 和 γ-分泌酶的表达，后者可对 ADAM10 进行蛋白水解加工。沉默 ADAM15 或 γ-分泌酶的表达会抑制逆转录和核进入之间的 HIV-1 复制。在这里，我们表明 ADAM10 的表达也支持 CD4(+) T 淋巴细胞中的复制。ADAM10 的细胞内结构域 (ICD) 与细胞质中的 HIV-1 前整合复合物 (PIC) 结合，并与 HIV-1 整合酶免疫沉淀和共定位，整合酶是 PIC 的关键组成部分。综上所述，我们的数据支持这样一种模型，即 ADAM15/γ-分泌酶对 ADAM10 的加工释放 ICD，然后 ICD 整合到 HIV-1 PIC 中以促进核转运。因此，这些研究表明 ADAM10 是一种在 HIV-1 进入核内之前抑制 HIV-1 的新的治疗靶标。
