Noninfectious retrovirus particles drive the APOBEC3/Rfv3 dependent neutralizing antibody response.
Noninfectious retrovirus particles drive the APOBEC3/Rfv3 dependent neutralizing antibody response.
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DOI：
10.1371/journal.ppat.1002284
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发表时间：
2011-10
期刊：
影响因子：
6.7
通讯作者：
Santiago ML
中科院分区：
文献类型：
--
作者：
Smith DS;Guo K;Barrett BS;Heilman KJ;Evans LH;Hasenkrug KJ;Greene WC;Santiago ML
脱氧胞苷脱氨酶 APOBEC3 家族的成员通过一种间接机制在体外对抗多种逆转录病毒，该机制需要病毒粒子掺入并抑制下一个靶细胞中的逆转录和/或负链转录物的超突变。这种间接限制机制对宿主的选择性优势尚不清楚，但通过研究 APOBEC3 体内功能可能会获得有价值的见解。 Apobec3 先前被证明编码 Rfv3，这是一种经典的抗性基因，通过促进更有效的中和抗体 (NAb) 反应来控制小鼠从致病性 Friend 逆转录病毒 (FV) 感染中恢复。根本机制不涉及 Apobec3 对 B 细胞功能的直接影响。在这里，我们表明，虽然 Apobec3 在急性 FV 感染期间降低了感染性病毒的滴度，但血浆病毒 RNA 负荷得以维持，表明体内非感染性颗粒的大量释放。血浆病毒粒子感染性的缺乏与早期逆转录过程中显着的进入后阻断有关，而不是与 G 至 A 超突变有关。 Apobec3 依赖性 NAb 反应与针对天然病毒颗粒的 IgG 结合滴度相关，但与去污剂裂解的病毒颗粒无关。这些发现表明，先天 Apobec3 限制通过维持具有天然 B 细胞表位的病毒粒子的高浓度来促进 NAB 反应，但在病毒粒子感染性较低的情况下。最后，发现 Apobec3 限制在体内是可饱和的，因为增加 FV 接种剂量会导致 Apobec3 抑制减少。类似地，通过调节 APOBEC3 表达来最大限度地释放非感染性颗粒可能会提高针对致病性人类逆转录病毒感染的体液免疫。 APOBEC3 基因家族的成员可以有效抑制多种逆转录病毒，包括 HIV-1。在细胞培养中，APOBEC3通过以下方式对抗逆转录病毒：（1）降低病毒粒子的感染性； (2) 在下一个靶细胞中诱导致命的 G-to-A 超突变。掺入病毒体并作用于下一个靶细胞的“间接”限制因子对宿主的选择性优势仍然是个谜。我们之前表明 Apobec3 编码 Rfv3，这是一种经典的抗性基因，控制小鼠体内针对 Friend 逆转录病毒感染的中和抗体反应。在这里，我们证明 Apobec3 在急性 FV 感染期间促进血浆中大量非感染性病毒粒子的释放，从而产生针对完整病毒粒子的更有效的抗体反应。因此，我们认为 APOBEC3 作为一种先天机制进化而来，以促进高浓度的逆转录病毒抗原以天然但非感染性的形式有效地引发中和抗体反应。这些发现可能对改善 HIV-1 特异性抗体反应具有重要意义。
Members of the APOBEC3 family of deoxycytidine deaminases counteract a broad range of retroviruses in vitro through an indirect mechanism that requires virion incorporation and inhibition of reverse transcription and/or hypermutation of minus strand transcripts in the next target cell. The selective advantage to the host of this indirect restriction mechanism remains unclear, but valuable insights may be gained by studying APOBEC3 function in vivo. Apobec3 was previously shown to encode Rfv3, a classical resistance gene that controls the recovery of mice from pathogenic Friend retrovirus (FV) infection by promoting a more potent neutralizing antibody (NAb) response. The underlying mechanism does not involve a direct effect of Apobec3 on B cell function. Here we show that while Apobec3 decreased titers of infectious virus during acute FV infection, plasma viral RNA loads were maintained, indicating substantial release of noninfectious particles in vivo. The lack of plasma virion infectivity was associated with a significant post-entry block during early reverse transcription rather than G-to-A hypermutation. The Apobec3-dependent NAb response correlated with IgG binding titers against native, but not detergent-lysed virions. These findings indicate that innate Apobec3 restriction promotes NAb responses by maintaining high concentrations of virions with native B cell epitopes, but in the context of low virion infectivity. Finally, Apobec3 restriction was found to be saturable in vivo, since increasing FV inoculum doses resulted in decreased Apobec3 inhibition. By analogy, maximizing the release of noninfectious particles by modulating APOBEC3 expression may improve humoral immunity against pathogenic human retroviral infections. Members of the APOBEC3 gene family can potently inhibit a broad range of retroviruses, including HIV-1. In cell culture, APOBEC3 counteracts retroviruses by: (1) reducing the infectivity of virions; and (2) inducing lethal G-to-A hypermutation in the next target cell. The selective advantage to the host of an ‘indirect’ restriction factor that is incorporated into virions and acts in the next target cell remains mysterious. We previously showed that Apobec3 encodes Rfv3, a classical resistance gene that controls the neutralizing antibody response against Friend retrovirus infection in mice. Here we demonstrate that Apobec3 promotes the release of substantial levels of noninfectious virions in the plasma during acute FV infection, resulting in a more potent antibody response directed against intact virions. Thus, we propose that APOBEC3 evolved as an innate mechanism to promote high concentrations of retrovirus antigen in a native but noninfectious form to effectively prime the neutralizing antibody response. These findings could have important implications for improving HIV-1 specific antibody responses.
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