Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada.
J Acquir Immune Defic Syndr. 2011 Feb 1;56(2):100-8. doi: 10.1097/QAI.0b013e3181fe9450.
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 human leukocyte antigen (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-integrase sequences from 58 elite controllers and 50 untreated chronic progressors were constructed, and replication capacity measured in vitro using a green fluorescent protein (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 with those from progressors (P < 0.0001). Among controllers, the most attenuated viruses were generated from individuals expressing HLA-B57 or B51. In viruses from B57+ progressors (n = 8), a significant inverse correlation was observed between B57-associated reverse transcriptase-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 seemed 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.
鉴定 HIV-1 精英控制者的病毒和宿主决定因素可能有助于为新的治疗和/或疫苗接种策略提供信息。先前，我们观察到控制者衍生的病毒复制能力降低，这表明 Gag 中人类白细胞抗原（HLA）I 类相关逃逸突变的适应性后果可能促成这种表型。本研究检查了精英控制器的 Pol 蛋白是否存在类似的功能缺陷。
构建了编码来自 58 名精英控制器和 50 名未经治疗的慢性进展者血浆 RNA 衍生逆转录酶-整合酶序列的重组 NL4-3 病毒，并使用绿色荧光蛋白（GFP）报告 T 细胞测定法在体外测量复制能力。对序列进行耐药性和 HLA 相关病毒多态性分析。
与进展者相比，控制器衍生的病毒显示出明显较低的复制能力（P < 0.0001）。在控制器中，表达 HLA-B57 或 B51 的个体产生的病毒衰减最严重。在 B57+进展者（n = 8）的病毒中，B57 相关逆转录酶-整合酶逃逸突变与复制能力之间存在显著负相关（R = -0.89；P = 0.003）；在 B*57+控制器衍生病毒中也观察到类似的趋势（n = 20，R = -0.36；P = 0.08）。
HIV-1 Pol 功能似乎在精英控制器中受到了损害。正如之前在 Gag 中观察到的那样，Pol 中 HLA 相关免疫压力可能有助于病毒衰减和随后的病毒血症控制。
