Reduced replication capacity of NL4-3 recombinant viruses encoding reverse transcriptase-integrase sequences from HIV-1 elite controllers.
Reduced replication capacity of NL4-3 recombinant viruses encoding reverse transcriptase-integrase sequences from HIV-1 elite controllers.
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DOI：
10.1097/qai.0b013e3181fe9450
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发表时间：
2011-02-01
期刊：
影响因子：
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通讯作者：
Brockman MA
中科院分区：
文献类型：
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作者：
Brumme ZL;Li C;Miura T;Sela J;Rosato PC;Brumme CJ;Markle TJ;Martin E;Block BL;Trocha A;Kadie CM;Allen TM;Pereyra F;Heckerman D;Walker BD;Brockman MA
识别HIV-1精英控制的病毒和宿主决定因素可能有助于提供新的治疗和/或疫苗接种策略。此前，我们观察到控制器衍生病毒的复制能力降低，这表明GAG中与HLAI类相关的逃逸突变的适合性结果可能有助于这种表型。这项研究考察了精英控制者的POL蛋白是否存在类似的功能缺陷。构建重组NL4-3病毒，编码来自58名精英控制者和50名未经治疗的慢性进展者的血浆RNA衍生的逆转录酶(RT)整合酶序列，并用GFP报告T细胞试验测定体外复制能力。对序列进行耐药性分析和人类白细胞抗原相关病毒的多态性分析。与进展型病毒相比，控制型病毒的复制能力明显较低(p<；0.0001)。在对照组中，最弱的病毒来自表达人类白细胞抗原-B*57或B*51的个体。在B*57+进展型病毒(N=8)中，与B*57相关的RT-整合酶逃逸突变与复制能力呈显著负相关(R=−0.89；p=0.003)；在B*57+控制型病毒(N=20，R=−0.36；p=0.08)中也观察到类似的趋势。精英控制员的HIV-1 POL功能似乎受到了损害。正如先前在GAG中观察到的那样，POL中与人类白细胞抗原相关的免疫压力可能有助于病毒减弱和随后的病毒血症的控制。
Identifying viral and host determinants of HIV-1 elite control may help inform novel therapeutic and/or vaccination strategies. Previously, we observed decreased replication capacity in controller-derived viruses suggesting that fitness consequences of HLA class I-associated escape mutations in Gag may contribute to this phenotype. This study examines whether similar functional defects occur in Pol proteins of elite controllers. Recombinant NL4-3 viruses encoding plasma RNA-derived Reverse Transcriptase (RT)-Integrase sequences from 58 elite controllers and 50 untreated chronic progressors were constructed and replication capacity measured in vitro using a GFP reporter T-cell assay. Sequences were analyzed for drug resistance and HLA-associated viral polymorphisms. Controller-derived viruses displayed significantly lower replication capacity compared to those from progressors (p<0.0001). Among controllers, the most attenuated viruses were generated from individuals expressing HLA-B*57 or B*51. In viruses from B*57+ progressors (N=8), a significant inverse correlation was observed between B*57-associated RT-Integrase escape mutations and replication capacity (R=−0.89; p=0.003); a similar trend was observed in B*57+ controller-derived viruses (N=20, R=−0.36; p=0.08). HIV-1 Pol function appeared to be compromised in elite controllers. As observed previously for Gag, HLA-associated immune pressure in Pol may contribute to viral attenuation and subsequent control of viremia.