irsiCaixa AIDS Research Institute, Badalona, Spain
irsiCaixa AIDS Research Institute, Badalona, Spain.
J Virol. 2018 May 29;92(12). doi: 10.1128/JVI.00346-18. Print 2018 Jun 15.
Viremic nonprogressors (VNPs) constitute a very scarce group of untreated human immunodeficiency virus type 1 (HIV-1)-infected individuals who maintain stable CD4 T cell counts despite high levels of HIV-1 replication. The specific factors associated with this atypical control of the HIV infection have been poorly described. Since specific T cell responses seem to be one of the main causes of HIV-1 control in elite controllers, we studied whether HIV-1 Gag-specific cytotoxic T lymphocyte (CTL) responses could also modulate disease control in VNPs. We characterized the immune responses from four VNPs compared to those of five standard progressors (SPs) during the first years of HIV-1 infection. We observed no differences in the breadth and frequency of Gag-specific cellular responses. Furthermore, we obtained 217 HIV-1 clonal sequences in which the viral variability of Gag increased over 3 years of infection for synonymous and nonsynonymous mutations in both VNPs and SPs. VNPs evolution rates in were comparable to SPs. This observation is in line with a similar accumulation of CTL putative escape mutations in Gag epitopes targeted by CTL responses. Altogether, the absence of viral pathogenesis in VNP individuals seems to be independent of HIV-Gag-specific CTL responses. This novel information guides to the study of alternative mechanism of HIV-1 pathogenesis control. Control of HIV infection has been widely studied in elite controllers or long-term nonprogressor models. However, there is a less-known group of individuals, termed viremic nonprogressors (VNPs), who maintain stable CD4 T cell counts despite high plasma viremia. The mechanisms involved in this remarkable control of HIV-1 pathogenesis clearly have implications for the development of new drugs and vaccines. We show here for the first time that VNPs have immune responses and HIV-gag evolution similar to those of standard progressors. Remarkably, we demonstrate that the mechanism of pathogenesis control in these individuals differs from some elite controllers that are reported to have improved immune control. This is noteworthy since it opens the door to new, as-yet-unknown mechanisms for HIV control. Our novel results advance the understanding of mechanisms involved in viremic nonprogression and suggest that there are alternative mechanisms to the adaptive immune responses for an effective control of viral pathogenesis.
病毒血症非进展者（VNPs）是一组非常罕见的未经治疗的人类免疫缺陷病毒 1 型（HIV-1）感染者，尽管 HIV-1 复制水平很高，但他们的 CD4 T 细胞计数仍保持稳定。与这种非典型 HIV 感染控制相关的具体因素描述甚少。由于特异性 T 细胞反应似乎是精英控制者控制 HIV-1 的主要原因之一，我们研究了 HIV-1 Gag 特异性细胞毒性 T 淋巴细胞（CTL）反应是否也能调节 VNPs 的疾病控制。我们比较了 HIV-1 感染的最初几年中 4 名 VNPs 与 5 名标准进展者（SPs）的免疫反应。我们没有观察到 Gag 特异性细胞反应的广度和频率有差异。此外，我们获得了 217 个 HIV-1 克隆序列，在 3 年的感染过程中，Gag 的病毒变异性增加了同义和非同义突变。VNPs 的进化率与 SPs 相当。这一观察结果与 CTL 反应靶向的 Gag 表位中 CTL 逃避突变的类似积累一致。总之，VNPs 个体中没有病毒发病机制似乎与 HIV-Gag 特异性 CTL 反应无关。这一新信息指导了 HIV-1 发病机制控制的替代机制的研究。在精英控制者或长期非进展者模型中，对 HIV 感染的控制已经进行了广泛的研究。然而，还有一个鲜为人知的群体，称为病毒血症非进展者（VNPs），他们尽管血浆病毒载量很高，但仍保持稳定的 CD4 T 细胞计数。这种对 HIV-1 发病机制的显著控制所涉及的机制显然对新药物和疫苗的开发具有重要意义。我们在这里首次表明，VNPs 具有与标准进展者相似的免疫反应和 HIV-gag 进化。值得注意的是，我们证明了这些个体中发病机制控制的机制与一些据报道具有改善免疫控制的精英控制者不同。这一点很重要，因为它为 HIV 控制的新的、未知的机制打开了大门。我们的新结果提高了对病毒血症非进展相关机制的理解，并表明除了适应性免疫反应之外，还有其他有效的控制病毒发病机制的机制。
