Protein Kinase Cθ Is a Specific Target for Inhibition of the HIV Type 1 Replication in CD4+ T Lymphocytes
Protein Kinase Cθ Is a Specific Target for Inhibition of the HIV Type 1 Replication in CD4+ T Lymphocytes
复制标题
DOI：
10.1074/jbc.m110.210443
复制
发表时间：
2011-08-05
影响因子：
4.8
通讯作者：
Coiras, Mayte
中科院分区：
文献类型：
--
作者：
Rosa Lopez-Huertas, Maria;Mateos, Elena;Coiras, Mayte
HIV-1基因组与CD4(+)T细胞的整合产生了具有较长半衰期的潜在蓄水池，这阻碍了感染的根除。控制病毒复制对于减少潜伏宿主的大小至关重要，主要是在HIV-1大规模感染CD4(+)T细胞的初次感染期间。在初次感染期间，在高效抗逆转录病毒治疗中加入免疫抑制剂，可以通过限制T细胞的激活来抑制HIV-1的复制，但这些药物显示出导致淋巴增生性疾病的潜在风险。选择性地抑制对T细胞功能至关重要的PKC theta将限制T细胞的激活和HIV-1的复制，而不会导致全身免疫抑制，因为PKC theta主要在T细胞中表达。因此，分析了剂量依赖的PKC theta抑制剂rotlerin对T细胞中HIV-1复制的影响。在MT-2(IC_(50)=5.2µM)和Jurkat(IC_(50)=2.2µM)细胞中，Rottlerin能使HIV-1复制减少20倍以上，在外周血淋巴细胞中(IC_(50)=4.4u M)减少4倍以上。观察到对PKC theta的选择性抑制，而不是PKC Delta或-Zeta
Integration of HIV-1 genome in CD4(+) T cells produces latent reservoirs with long half-life that impedes the eradication of the infection. Control of viral replication is essential to reduce the size of latent reservoirs, mainly during primary infection when HIV-1 infects CD4(+) T cells massively. The addition of immunosuppressive agents to highly active antiretroviral therapy during primary infection would suppress HIV-1 replication by limiting T cell activation, but these agents show potential risk for causing lymphoproliferative disorders. Selective inhibition of PKC theta, crucial for T cell function, would limit T cell activation and HIV-1 replication without causing general immunosuppression due to PKC theta being mostly expressed in T cells. Accordingly, the effect of rottlerin, a dose-dependent PKC theta inhibitor, on HIV-1 replication was analyzed in T cells. Rottlerin was able to reduce HIV-1 replication more than 20-fold in MT-2 (IC50 = 5.2 mu M) and Jurkat (IC50 = 2.2 mu M) cells and more than 4-fold in peripheral blood lymphocytes (IC50 = 4.4 mu M). Selective inhibition of PKC theta, but not PKC delta or -zeta, was observed at