The Envelope Gene of Transmitted HIV-1 Resists a Late Interferon Gamma-Induced Block.
The Envelope Gene of Transmitted HIV-1 Resists a Late Interferon Gamma-Induced Block.
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DOI：
10.1128/jvi.02254-16
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发表时间：
2017-04-01
影响因子：
5.4
通讯作者：
Wilson SJ
中科院分区：
文献类型：
--
作者：
Rihn SJ;Foster TL;Busnadiego I;Aziz MA;Hughes J;Neil SJD;Wilson SJ
I型干扰素（IFN）信号传导产生抗病毒状态，其可能在限制HIV-1传播中起重要作用，并有助于定义随后的AIDS发病机制。II型IFN（IFN-γ）也诱导抗病毒状态，但通常主要被认为是免疫调节细胞因子。我们报道了IFN-γ刺激可以诱导一种抗病毒状态，这种状态既不同于I型干扰素，又可以有效地抑制原代CD 4 + T细胞和许多人类细胞系中的HIV-1。引人注目的是，我们发现，传播/创始人（TF）HIV-1病毒可以抵抗由II型IFN诱导的晚期阻断，并且使用嵌合IFN-γ敏感/抗性病毒表明干扰素抗性映射到env基因。同时，体外进化也表明，在包膜中的一个单一的氨基酸取代可以赋予实质性的抵抗干扰素介导的抑制。因此，传播的HIV-1的env基因赋予对晚期阻断的抗性，所述晚期阻断在表型上不同于先前描述的由env抵抗的阻断，并且因此由人CD 4 + T细胞和细胞系中的未知IFN-γ刺激因子介导。这一重要的未确定的块可能在限制HIV-1传播方面发挥关键作用。重要性人类免疫系统可以通过干扰素（IFN）信号阻止入侵病原体。这种信号的一个结果是细胞进入抗病毒状态，增加了数百种可以抑制病毒复制和传播的防御水平。大多数HIV-1感染是由单个病毒颗粒（传播/创始者）引起的，该病毒颗粒使其通过这些防御并定殖宿主。因此，创始者病毒被假设为是一个相对的干扰素耐药实体。在这里，我们表明，某些HIV-1包膜基因具有意想不到的能力，以抵抗特定的人类防御介导的不同类型的干扰素。引人注目的是，来自创始人HIV-1病毒的包膜基因比来自普通HIV-1实验室菌株的相应基因更善于逃避这些防御。因此，这些防御可以在限制HIV-1的传播中发挥作用，并且可以选择对这种IFN介导的抑制具有抗性的传播病毒。
Type I interferon (IFN) signaling engenders an antiviral state that likely plays an important role in constraining HIV-1 transmission and contributes to defining subsequent AIDS pathogenesis. Type II IFN (IFN-γ) also induces an antiviral state but is often primarily considered to be an immunomodulatory cytokine. We report that IFN-γ stimulation can induce an antiviral state that can be both distinct from that of type I interferon and can potently inhibit HIV-1 in primary CD4+ T cells and a number of human cell lines. Strikingly, we find that transmitted/founder (TF) HIV-1 viruses can resist a late block that is induced by type II IFN, and the use of chimeric IFN-γ-sensitive/resistant viruses indicates that interferon resistance maps to the env gene. Simultaneously, in vitro evolution also revealed that just a single amino acid substitution in the envelope can confer substantial resistance to IFN-mediated inhibition. Thus, the env gene of transmitted HIV-1 confers resistance to a late block that is phenotypically distinct from blocks previously described to be resisted by env and is therefore mediated by unknown IFN-γ-stimulated factor(s) in human CD4+ T cells and cell lines. This important unidentified block could play a key role in constraining HIV-1 transmission. IMPORTANCE The human immune system can hinder invading pathogens through interferon (IFN) signaling. One consequence of this signaling is that cells enter an antiviral state, increasing the levels of hundreds of defenses that can inhibit the replication and spread of viruses. The majority of HIV-1 infections result from a single virus particle (the transmitted/founder) that makes it past these defenses and colonizes the host. Thus, the founder virus is hypothesized to be a relatively interferon-resistant entity. Here, we show that certain HIV-1 envelope genes have the unanticipated ability to resist specific human defenses mediated by different types of interferons. Strikingly, the envelope gene from a founder HIV-1 virus is far better at evading these defenses than the corresponding gene from a common HIV-1 lab strain. Thus, these defenses could play a role in constraining the transmission of HIV-1 and may select for transmitted viruses that are resistant to this IFN-mediated inhibition.