LOW-LEVELS OF DEOXYNUCLEOTIDES IN PERIPHERAL-BLOOD LYMPHOCYTES - A STRATEGY TO INHIBIT HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REPLICATION
LOW-LEVELS OF DEOXYNUCLEOTIDES IN PERIPHERAL-BLOOD LYMPHOCYTES - A STRATEGY TO INHIBIT HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REPLICATION
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DOI：
10.1073/pnas.90.19.8925
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发表时间：
1993-10-01
影响因子：
11.1
通讯作者：
LORI, F
中科院分区：
文献类型：
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作者：
GAO, WY;CARA, A;LORI, F
研究了人免疫缺陷病毒1型（HIV-1）在静止和活化的外周血淋巴细胞（PBL）中的病毒DNA合成。不完整的病毒DNA（先前证明与HIV-1病毒体相关）由HIV-1病毒体携带进入静止和活化的PBLS，有助于在这些细胞中形成早期病毒DNA库。病毒DNA随后完成，但与刺激的PBL相比，在静止的PBL中仅极其缓慢和低效。我们发现，这与显著较低水平的dNTP底物相比，活化的PBL在静止。在这些低dNTP浓度下，HIV-1逆转录酶以部分分布的方式起作用。将dNTP浓度从静止PBL的水平增加到活化PBL的水平是逆转录酶的进行性作用，这反过来又刺激全长DNA的快速有效形成。此外，刺激的PBL的羟基脲处理降低dNTP水平和DNA合成速率至与静止PBL相当的水平。因此，我们的数据表明，低水平的dNTP可以解释为什么HIV-1 DNA的合成缓慢，无效的静止PBL，并建议，药理学诱导低dNTP水平代表了一种治疗方法抑制HIV-1复制。
Human immunodeficiency virus type 1 (HIV-1) viral DNA synthesis in quiescent and activated peripheral blood lymphocytes (PBLs) was studied. Incomplete viral DNA (previously demonstrated to be associated with HIV-1 virions) is carried by HIV-1 virions into quiescent and activated PBLS, contributing to the formation of an early viral DNA pool in these cells. The viral DNA is subsequently completed but only extremely slowly and inefficiently in quiescent PBLs compared to that in stimulated PBLs. We find that this correlates with significantly lower levels of dNTP substrates in quiescent compared to activated PBLs. At these low dNTP concentrations, HIV-1 reverse transcriptase acts in a partially distributive manner. Increasing dNTP concentrations from the levels of quiescent PBLs to the levels of activated pBLs the processive action of reverse transcriptase, which in turn stimulates rapid and efficient formation of full-length DNA. Furthermore, hydroxyurea treatment of stimulated PBLs decreases the dNTP levels and the DNA synthesis rate to levels comparable to quiescent PBLs. Our data therefore indicate that low levels of dNTP may explain why HIV-1 DNA is synthesized slowly and inefficiently in quiescent PBLs and suggest that pharmacologic induction of low dNTP levels represents a therapeutic approach for inhibition of HIV-1 replication.