Architecture et Réactivité de l'ARN-UPR 9002, IBMC, CNRS, Université de Strasbourg, Strasbourg, France.
Interdisciplinary Thematic Institute (ITI) InnoVec, Université de Strasbourg, Strasbourg, France.
PLoS Pathog. 2023 Mar 30;19(3):e1011207. doi: 10.1371/journal.ppat.1011207. eCollection 2023 Mar.
Transmissions of simian viruses to humans has originated the different groups of HIV-1. We recently identified a functional motif (CLA), in the C-terminal domain of the integrase, essential for integration in HIV-1 group M. Here, we found that the motif is instead dispensable in group O isolates, because of the presence, in the N-terminal domain of HIV-1 O of a specific sequence, Q7G27P41H44, that we define as the NOG motif. Alterations of reverse transcription and of 3' processing observed by mutating the CLA motif of IN M are fully rescued to wt levels by inserting the sequence of the NOG motif in the N-ter of the protein. These results indicate that the two motifs (CLA and NOG) functionally complement each other and a working model accounting for these observations is proposed. The establishment of these two alternative motifs seems to be due to the different phylogenetic origin and history of these two groups. Indeed, the NOG motif is already present in the ancestor of group O (SIVgor) while it is absent from SIVcpzPtt, the ancestor of group M. The CLA motif, instead, seems to have emerged after SIVcpzPtt has been transferred to humans, since no conservation is found at the same positions in these simian viruses. These results show the existence of two-group specific motifs in HIV-1 M and O integrases. In each group, only one of the motifs is functional, potentially leading the other motif to diverge from its original function and, in an evolutionary perspective, assist other functions of the protein, further increasing HIV genetic diversity.
灵长类病毒向人类的传播导致了不同组别的 HIV-1 的出现。我们最近在整合酶的 C 末端结构域中发现了一个功能性基序（CLA），它对 HIV-1 组 M 的整合至关重要。然而，我们发现该基序在组 O 分离株中是可有可无的，因为在 HIV-1 O 的 N 末端结构域中存在一个特定的序列 Q7G27P41H44，我们将其定义为 NOG 基序。通过突变 IN M 的 CLA 基序观察到的逆转录和 3' 加工的改变，通过将 NOG 基序的序列插入到蛋白的 N 端，完全恢复到 wt 水平。这些结果表明，这两个基序（CLA 和 NOG）在功能上是互补的，并提出了一个解释这些观察结果的工作模型。这两个替代基序的建立似乎是由于这两个组的不同进化起源和历史。事实上，NOG 基序已经存在于组 O 的祖先（SIVgor）中，而在组 M 的祖先 SIVcpzPtt 中却不存在。相反，CLA 基序似乎是在 SIVcpzPtt 转移到人类之后出现的，因为在这些灵长类病毒中，在相同位置没有保守性。这些结果表明，HIV-1 M 和 O 整合酶中存在两种组特异性基序。在每个组中，只有一个基序是功能性的，这可能导致另一个基序从其原始功能中分化出来，并且从进化的角度来看，辅助蛋白质的其他功能，进一步增加了 HIV 的遗传多样性。
