Drouin Aurélie, Migraine Julie, Durand Marie-Alice, Moreau Alain, Burlaud-Gaillard Julien, Beretta Maxime, Roingeard Philippe, Bouvin-Pley Mélanie, Braibant Martine
Université de Tours et CHRU de Tours, Inserm U1259, Tours, France.
Université de Tours et CHRU de Tours, Plateforme IBiSA de Microscopie Electronique, Tours, France.
J Virol. 2021 Mar 1;95(5). doi: 10.1128/JVI.01994-20. Epub 2020 Dec 9.
Interferon-induced transmembrane protein 3 (IFITM3) is a cellular factor that reduces HIV-1 infectivity by an incompletely understood mechanism. We show here that viruses differing only in the envelope glycoprotein (Env) expressed on their surface have different sensitivities to IFITM3. Measurements of the sensitivity of viruses to neutralizing antibodies showed that IFITM3 increased the sensitivity of IFITM3-sensitive viruses to PG16, which targets the V1V2 loop, suggesting that IFITM3 promotes exposure of the PG16 epitope of IFITM3-sensitive viruses. Exchanges of V1V2 loops between the Env proteins of sensitive and resistant viruses revealed that V1V2 and V3 act together to modulate viral sensitivity to IFITM3. Co-immunoprecipitation experiments showed that IFITM3 interacted with both the precursor (gp160) and cleaved (gp120) forms of Env from IFITM3-sensitive viruses, but only with the precursor (gp160) form of Env from IFITM3-resistant viruses. This finding suggests that the interaction between the Env of resistant viruses and IFITM3 was inhibited once Env had been processed in the Golgi apparatus. This hypothesis was supported by immunofluorescence experiments, which showed a strong colocalization of IFITM3 with the Env of sensitive viruses, but only weak colocalization with the Env of resistant viruses on the plasma membrane of virus-producing cells. Together, these results indicate that IFITM3 interacts with Env, inducing conformational changes that may decrease viral infectivity. This antiviral action is, nevertheless, modulated by the nature of the Env, in particular its V1V2 and V3 loops, which after maturation may be able to escape this interaction. Interferon-induced transmembrane protein 3 (IFITM3) is a cellular factor that reduces HIV-1 infectivity by an incompletely understood mechanism. This study aimed to elucidate the role of the HIV-1 envelope glycoprotein (Env) in determining viral susceptibility to IFITM3. We found that viruses differing only in Env expressed on their surface had different sensitivities to IFITM3. By comparing the Env proteins of viruses that were highly sensitive or resistant to IFITM3, we obtained new insight in the mechanisms by which HIV-1 escapes this protein. We showed that IFITM3 interacts with the Env protein of sensitive viruses in virion-producing cells, inducing conformational changes that may decrease viral infectivity. However, this antiviral action is modulated by the nature of Env, particularly the V1V2 and V3 loops, which may be able to escape this interaction after processing in the Golgi.
干扰素诱导跨膜蛋白3（IFITM3）是一种细胞因子，其通过一种尚未完全了解的机制降低HIV-1的感染性。我们在此表明，仅在其表面表达的包膜糖蛋白（Env）不同的病毒对IFITM3具有不同的敏感性。对病毒对中和抗体敏感性的测量表明，IFITM3增加了对IFITM3敏感病毒对靶向V1V2环的PG16的敏感性，这表明IFITM3促进了对IFITM3敏感病毒的PG16表位的暴露。敏感病毒和抗性病毒的Env蛋白之间V1V2环的交换表明，V1V2和V3共同作用以调节病毒对IFITM3的敏感性。免疫共沉淀实验表明，IFITM3与来自对IFITM3敏感病毒的Env的前体（gp160）和裂解形式（gp120）相互作用，但仅与来自对IFITM3抗性病毒的Env的前体（gp160）形式相互作用。这一发现表明，一旦Env在高尔基体中被加工，抗性病毒的Env与IFITM3之间的相互作用就会受到抑制。免疫荧光实验支持了这一假设，该实验表明IFITM3与敏感病毒的Env在病毒产生细胞的质膜上有很强的共定位，但与抗性病毒的Env只有较弱的共定位。总之，这些结果表明IFITM3与Env相互作用，诱导可能降低病毒感染性的构象变化。然而，这种抗病毒作用受到Env性质的调节，特别是其V1V2和V3环，在成熟后可能能够逃避这种相互作用。干扰素诱导跨膜蛋白3（IFITM3）是一种细胞因子，其通过一种尚未完全了解的机制降低HIV-1的感染性。本研究旨在阐明HIV-1包膜糖蛋白（Env）在决定病毒对IFITM3易感性中的作用。我们发现仅在其表面表达的Env不同的病毒对IFITM3具有不同的敏感性。通过比较对IFITM3高度敏感或抗性的病毒的Env蛋白，我们对HIV-1逃避这种蛋白的机制有了新的认识。我们表明，IFITM3在病毒产生细胞中与敏感病毒的Env蛋白相互作用，诱导可能降低病毒感染性的构象变化。然而，这种抗病毒作用受到Env性质的调节，特别是V1V2和V3环，它们在高尔基体中加工后可能能够逃避这种相互作用。
