Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, 53226, USA.
Cell Host Microbe. 2011 Feb 17;9(2):103-14. doi: 10.1016/j.chom.2011.01.006.
Infection with the β-herpesvirus human cytomegalovirus (HCMV) is lifelong, causing limited disease in healthy adults, but life threatening in immunocompromised individuals. The viral kinase pUL97, a functional ortholog of cellular cyclin-dependent kinases (CDKs), is critical for HCMV replication and a target for antiviral drug development. Upon kinase inhibition, drug-resistant strains emerge with mutations in UL27, an HCMV gene of unknown function. Using a proteomics approach, we discovered that pUL27 is necessary and sufficient to degrade Tip60, a host acetyltransferase and interacting partner of HIV Tat. Consistent with this, the expression of Tat restored antiviral inhibition of an otherwise resistant HCMV strain. The functional consequence of Tip60 degradation was the induction of the CDK inhibitor p21(Waf1/Cip1) and cell-cycle arrest, representing changes necessary for the antiviral effects of pUL97 inhibition. Consequently, either increasing p21(Waf1/Cip1) expression or decreasing Tip60 levels improved the antiviral activity of the HCMV kinase inhibitor maribavir.
β-疱疹病毒人类巨细胞病毒（HCMV）的感染是终身的，在健康成年人中引起的疾病有限，但在免疫功能低下的个体中则具有生命威胁。病毒激酶 pUL97 是细胞周期蛋白依赖性激酶（CDKs）的功能同源物，对 HCMV 的复制至关重要，也是抗病毒药物开发的目标。在激酶抑制后，会出现具有 UL27 突变的耐药株，而 UL27 是一种功能未知的 HCMV 基因。通过蛋白质组学方法，我们发现 pUL27 是降解 Tip60 所必需和充分的，Tip60 是一种宿主乙酰转移酶和 HIV Tat 的相互作用伙伴。与此一致的是，Tat 的表达恢复了 otherwise resistant HCMV 株的抗病毒抑制作用。Tip60 降解的功能后果是诱导 CDK 抑制剂 p21（Waf1/Cip1）和细胞周期停滞，这代表了 pUL97 抑制的抗病毒作用所必需的变化。因此，增加 p21（Waf1/Cip1）的表达或降低 Tip60 水平均可提高 HCMV 激酶抑制剂 maribavir 的抗病毒活性。
