Highly active antiretroviral therapies are effective against HIV-1 cell-to-cell transmission.
Highly active antiretroviral therapies are effective against HIV-1 cell-to-cell transmission.
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DOI：
10.1371/journal.ppat.1003982
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发表时间：
2014-02
期刊：
影响因子：
6.7
通讯作者：
Mothes W
中科院分区：
文献类型：
--
作者：
Agosto LM;Zhong P;Munro J;Mothes W
HIV-1 细胞间传播的病毒传播效率比无细胞传播高 2-3 个数量级。在细胞与细胞接触部位观察到的高局部感染复数（MOI）可能会降低抗逆转录病毒疗法（ART）的疗效。在这里，我们测试了常用的抗逆转录病毒抑制剂对细胞间和无细胞 HIV-1 传播的功效。我们证明，虽然一些核苷类似物逆转录酶抑制剂（NRTI）对 HIV-1 细胞间传播的效果较差，但大多数非核苷类似物逆转录酶抑制剂（NNRTI）、进入抑制剂和蛋白酶抑制剂仍然非常有效。此外，当联合应用时，效果不佳的 NRTI 会变得非常有效，这解释了 ART 在临床环境中的有效性。通过研究其潜在机制，我们观察到单个药物和药物组合干扰 HIV-1 细胞间传播的能力与其对抗高病毒 MOI 的有效性之间存在严格相关性。我们的结果表明，抑制高病毒 MOI 的能力是有效 ART 方案的一个特征，在设计新型抗病毒疗法时应考虑这一参数。 HIV-1 细胞间传播因其在艾滋病发病机制中的潜在作用而引起人们的兴趣。最近有人提出，抗逆转录病毒疗法在细胞间传播过程中会失败，因为大量颗粒在细胞间接触部位转移。然而，这些发现与 ART 成功抑制 HIV 阳性患者逆转录病毒复制的临床观察结果形成鲜明对比。因此，许多人将这一观察结果解释为 HIV-1 细胞间传播与临床无关。在这里我们表明这种解释可能是不正确的。通过系统地测试常用的抗逆转录病毒抑制剂对细胞间和无细胞 HIV-1 传播的功效，我们证明，虽然一些 NRTI 效果较差，但大多数 NNRTI、进入抑制剂和蛋白酶抑制剂仍然非常有效。此外，NRTI 在联合使用时变得非常有效，从而支持了 HAART 在临床环境中已知的有效性。有趣的是，单个药物和组合干扰 HIV-1 细胞间传播的能力与其对抗高病毒 MOI 的有效性相关。我们的结果表明，在 HIV-1 细胞间传播过程中抑制高病毒 MOI 的能力是现有 ART 方案的一个关键特征，在设计新型抗病毒疗法时应对其进行测试。
HIV-1 cell-to-cell transmission allows for 2–3 orders of magnitude more efficient viral spread than cell-free dissemination. The high local multiplicity of infection (MOI) observed at cell-cell contact sites may lower the efficacy of antiretroviral therapies (ART). Here we test the efficacy of commonly used antiretroviral inhibitors against cell-to-cell and cell-free HIV-1 transmission. We demonstrate that, while some nucleoside-analog reverse transcriptase inhibitors (NRTI) are less effective against HIV-1 cell-to-cell transmission, most non-nucleoside-analog reverse transcriptase inhibitors (NNRTI), entry inhibitors and protease inhibitors remain highly effective. Moreover, poor NRTIs become highly effective when applied in combinations explaining the effectiveness of ART in clinical settings. Investigating the underlying mechanism, we observe a strict correlation between the ability of individual drugs and combinations of drugs to interfere with HIV-1 cell-to-cell transmission, and their effectiveness against high viral MOIs. Our results suggest that the ability to suppress high viral MOI is a feature of effective ART regimens and this parameter should be considered when designing novel antiviral therapies. HIV-1 cell-to-cell transmission has gained interest due to its potential role in AIDS pathogenesis. It has recently been suggested that antiretroviral therapies fail during cell-to-cell transmission because of the high number of particles transferred at sites of cell-cell contacts. However, these findings stand in contrast with the clinical observation that ART is successful in suppressing retroviral replication in HIV-positive patients. Consequently, many interpreted this observation to suggest that HIV-1 cell-to-cell transmission is not clinically relevant. Here we show that this interpretation is likely incorrect. By systematically testing the efficacy of commonly used antiretroviral inhibitors against cell-to-cell and cell-free HIV-1 transmission, we demonstrate that, while some NRTIs are less effective, most NNRTIs, entry inhibitors and protease inhibitors remain highly effective. Moreover, NRTIs become highly effective when combined, thus supporting the known effectiveness of HAART in clinical settings. Interestingly, the ability of individual drugs and combinations to interfere with HIV-1 cell-to-cell transmission correlates with their effectiveness against high viral MOIs. Our results suggest that the ability to suppress the high viral MOI during HIV-1 cell-to-cell transmission is a critical feature of existing ART regimens that should be tested when designing novel antiviral therapies.
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影响因子：
5.4
作者：
DIMITROV, DS;WILLEY, RL;MARTIN, MA
通讯作者：
MARTIN, MA
影响因子：
158.5
作者：
Gulick, RM;Mellors, JW;Chodakewitz, JA
通讯作者：
Chodakewitz, JA
DOI：
10.1097/qad.0b013e3283632ec4
发表时间：
2013-09-10
期刊：
AIDS (London, England)
影响因子：
--
作者：
Duncan CJ;Russell RA;Sattentau QJ
通讯作者：
Sattentau QJ
影响因子：
2.9
作者：
Arion, D;Kaushik, N;Parniak, MA
通讯作者：
Parniak, MA
影响因子：
5.4
作者：
ADACHI, A;GENDELMAN, HE;MARTIN, MA
通讯作者：
MARTIN, MA