Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Sci Transl Med. 2021 Jan 13;13(576). doi: 10.1126/scitranslmed.abd8179.
Type 1 interferons (IFN-I) are potent innate antiviral effectors that constrain HIV-1 transmission. However, harnessing these cytokines for HIV-1 cure strategies has been hampered by an incomplete understanding of their antiviral activities at later stages of infection. Here, we characterized the IFN-I sensitivity of 500 clonally derived HIV-1 isolates from the plasma and CD4 T cells of 26 individuals sampled longitudinally after transmission or after antiretroviral therapy (ART) and analytical treatment interruption. We determined the concentration of IFNα2 and IFNβ that reduced viral replication in vitro by 50% (IC) and found consistent changes in the sensitivity of HIV-1 to IFN-I inhibition both across individuals and over time. Resistance of HIV-1 isolates to IFN-I was uniformly high during acute infection, decreased in all individuals in the first year after infection, was reacquired concomitant with CD4 T cell loss, and remained elevated in individuals with accelerated disease. HIV-1 isolates obtained by viral outgrowth during suppressive ART were relatively IFN-I sensitive, resembling viruses circulating just before ART initiation. However, viruses that rebounded after treatment interruption displayed the highest degree of IFNα2 and IFNβ resistance observed at any time during the infection course. These findings indicate a dynamic interplay between host innate responses and the evolving HIV-1 quasispecies, with the relative contribution of IFN-I to HIV-1 control affected by both ART and analytical treatment interruption. Although elevated at transmission, host innate pressures are the highest during viral rebound, limiting the viruses that successfully become reactivated from latency to those that are IFN-I resistant.
I 型干扰素（IFN-I）是强大的先天抗病毒效应物，可限制 HIV-1 的传播。然而，由于对感染后期这些细胞因子的抗病毒活性认识不完整，利用这些细胞因子来实现 HIV-1 的治愈策略受到了阻碍。在这里，我们对来自 26 名个体的血浆和 CD4 T 细胞中 500 个克隆衍生的 HIV-1 分离物的 IFN-I 敏感性进行了特征描述，这些个体在传播后或接受抗逆转录病毒治疗（ART）和分析性治疗中断后进行了纵向采样。我们确定了 IFNα2 和 IFNβ 的浓度，这些浓度可使病毒在体外复制减少 50%（IC），并发现 HIV-1 对 IFN-I 抑制的敏感性在个体间和随时间的推移都发生了一致的变化。在急性感染期间，HIV-1 对 IFN-I 的耐药性普遍较高，在感染后第一年所有个体的耐药性均降低，与 CD4 T 细胞丢失同时重新获得，在疾病加速的个体中仍保持升高。在抑制性 ART 期间通过病毒扩增获得的 HIV-1 分离物相对 IFN-I 敏感，类似于在开始 ART 之前循环的病毒。然而，在治疗中断后反弹的病毒表现出在感染过程中任何时候观察到的最高程度的 IFNα2 和 IFNβ 耐药性。这些发现表明宿主先天反应与不断进化的 HIV-1 准种之间存在动态相互作用，IFN-I 对 HIV-1 控制的相对贡献受到 ART 和分析性治疗中断的影响。尽管在传播时升高，但宿主先天压力在病毒反弹时最高，限制了从潜伏状态成功重新激活的病毒对 IFN-I 的耐药性。
