Limited sequence variation and similar phenotypic characteristics of HIV-1 subtype C Gag variants derived from the reservoir and pre-therapy plasma

Latent reservoirs are a barrier to achieving long-term remission of HIV, as the dormant virus can be reactivated if therapy is discontinued. A combination approach of latency reversal agents and a cytotoxic T lymphocyte (CTL)-based therapeutic vaccine or other immunomodulatory agents to eliminate the reactivated viruses, is being explored for virus eradication. Investigation of whether viral variants present in the reservoir differ from those circulating in peripheral blood prior to treatment initiation, could better inform immune-based interventions for HIV cure. Further, most previous reservoir studies focussed on peripheral blood, however it is also relevant to study the reservoir in tissues. Here, we characterised the viral variants in the peripheral blood and lymph node reservoir in comparison to those in pre-therapy plasma. We focussed on the Gag protein as it is a major target of CTL-based therapeutic vaccines and influences replication ability of the virus as well as susceptibility to antiviral cytokines. Results showed limited novel mutations and a similar extent of CTL escape in the reservoir variants compared to the pre-therapy variants. The novel Gag mutations in the reservoir variants did not significantly alter virus characteristics overall, and are therefore unlikely to affect effectiveness of immune-based interventions for virus eradication.

潜伏病毒库是实现HIV长期缓解的一大障碍，因为一旦停止治疗，休眠的病毒即可被重新激活。目前，学界正在探索联合应用潜伏逆转剂与基于细胞毒性T淋巴细胞（cytotoxic T lymphocyte, CTL）的治疗性疫苗或其他免疫调节制剂以清除被激活病毒的策略，以期实现HIV根除。探究潜伏病毒库中的病毒变异株与治疗启动前在外周血中循环的病毒变异株是否存在差异，能够为优化HIV治愈相关的免疫干预策略提供更充分的依据。此外，既往多数病毒库研究均聚焦于外周血样本，但对组织内病毒库的研究同样具有重要价值。本研究对外周血与淋巴结病毒库中的病毒变异株进行了表征，并与治疗前血浆中的病毒变异株开展对比分析。本研究选取Gag蛋白作为研究靶点，原因在于其是基于CTL的治疗性疫苗的主要靶标，同时可影响病毒的复制能力以及对抗病毒细胞因子的易感性。研究结果显示，与治疗前的病毒变异株相比，病毒库变异株的新发突变数量有限，且CTL逃逸的程度相近。病毒库变异株中出现的新发Gag突变整体上并未显著改变病毒的生物学特性，因此不太会影响针对HIV根除的免疫干预策略的有效性。