Defective HIV-1 Proviruses Are Expressed and Can Be Recognized by Cytotoxic T Lymphocytes, which Shape the Proviral Landscape.
Defective HIV-1 Proviruses Are Expressed and Can Be Recognized by Cytotoxic T Lymphocytes, which Shape the Proviral Landscape.
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DOI：
10.1016/j.chom.2017.03.008
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发表时间：
2017-04-12
影响因子：
30.3
通讯作者：
Ho YC
中科院分区：
文献类型：
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作者：
Pollack RA;Jones RB;Pertea M;Bruner KM;Martin AR;Thomas AS;Capoferri AA;Beg SA;Huang SH;Karandish S;Hao H;Halper-Stromberg E;Yong PC;Kovacs C;Benko E;Siliciano RF;Ho YC
尽管进行了抗逆转录病毒治疗，HIV-1仍然存在于记忆性CD 4 + T细胞中，从而形成了治愈的障碍。大多数HIV-1前病毒是有缺陷的，被认为与临床无关。使用来自HIV-1感染个体的细胞和重建的患者来源的缺陷前病毒，我们表明，缺陷前病毒可以转录成RNA，剪接和翻译。具有缺陷的主要剪接供体（MSD）的前病毒可以激活新的剪接位点以产生HIV-1转录物，并且具有这些前病毒的细胞可以被HIV-1特异性细胞毒性T淋巴细胞（CTL）识别。此外，具有在CTL表位上游含有致死突变的前病毒的细胞也可以潜在地通过异常翻译被CTL识别。因此，CTL可以通过优先靶向具有特定类型缺陷前病毒的细胞来改变HIV-1前病毒的景观。此外，在测量HIV-1潜伏期逆转时需要考虑缺陷前病毒的表达。
Despite antiretroviral therapy, HIV-1 persists in memory CD4+ T cells creating a barrier to cure. The majority of HIV-1 proviruses are defective and considered clinically irrelevant. Using cells from HIV-1-infected individuals and reconstructed patient-derived defective proviruses, we show that defective proviruses can be transcribed into RNAs that are spliced and translated. Proviruses with defective major splice donors (MSDs) can activate novel splice sites to produce HIV-1 transcripts and cells with these proviruses can be recognized by HIV-1-specific cytotoxic T lymphocytes (CTLs). Further, cells with proviruses containing lethal mutations upstream of CTL epitopes can also be recognized by CTLs potentially through aberrant translation. Thus, CTLs may change the landscape of HIV-1 proviruses by preferential targeting cells with specific types of defective proviruses. Additionally, the expression of defective proviruses will need to be considered in the measurement of HIV-1 latency reversal.