Premature Activation of the HIV RNase H Drives the Virus into Suicide: A Novel Microbicide?
Premature Activation of the HIV RNase H Drives the Virus into Suicide: A Novel Microbicide?
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DOI：
10.1089/aid.2012.0067
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发表时间：
2012-11-01
影响因子：
1.5
通讯作者：
Moelling, Karin
中科院分区：
文献类型：
--
作者：
Broecker, Felix;Andrae, Karsten;Moelling, Karin
艾滋病毒的性传播是艾滋病毒在非洲和第三世界传播的主要原因，也是一个未得到满足的医疗需求。最近，杀微生物剂引起了人们的注意，因为它们可以让女性保护自己和后代。我们正在开发四种逆转录病毒酶之一，核糖核酸酶H，RNase H，作为杀微生物剂的新方法。它是唯一一种尚未被抗逆转录病毒治疗靶向的HIV酶。该酶与逆转录酶（RT）连接并水解RNA-DNA杂合体的RNA部分。RNase H位于病毒颗粒内，通常在细胞内病毒复制期间发挥作用。在这里，我们表明，过早地激活病毒颗粒内的RNase H会破坏病毒基因组并消除病毒的感染性。抗病毒化合物由合成的寡脱氧核苷酸（ODN）组成，它为颗粒内的RNase H创造了人工RNA-DNA杂交底物。在包括人源化SCID小鼠和小鼠阴道的小鼠模型中分析该化合物。感染减少了1000倍或可以完全预防。该化合物适合作为杀微生物剂或预防母婴传播。
Sexual transmission of HIV is the major cause of spread of HIV in Africa and the Third World and is an unmet medical need. Recently, microbicides have attracted attention because they allow females to protect themselves and their offspring. We are exploiting one of the four retroviral enzymes, the ribonuclease H, RNase H, as a novel approach for a microbicide. It is the only enzyme of HIV not yet targeted by antiretroviral therapy. The enzyme is linked to the reverse transcriptase (RT) and hydrolyzes the RNA moiety of RNA-DNA hybrids. The RNase H is located inside virus particles and normally functions during viral replication inside cells. Here we show that activating the RNase H prematurely inside the virus particles destroys the viral genome and abrogates viral infectivity. The antiviral compound consists of a synthetic oligodeoxynucleotide (ODN), which creates an artificial RNA-DNA hybrid substrate for the RNase H inside the particle. The compound was analyzed in mouse models including humanized SCID mice and the vagina of mice. Infection was reduced up to 1000-fold or could be completely prevented. The compound is suitable as microbicide or to prevent mother-to-child transmission.