Dynamic Interaction between STLV-1 Proviral Load and T-Cell Response during Chronic Infection and after Immunosuppression in Non-Human Primates

We used mandrills (Mandrillus sphinx) naturally infected with simian T-cell leukemia virus type 1 (STLV-1) as a model for evaluating the influence of natural STLV-1 infection on the dynamics and evolution of the immune system during chronic infection. Furthermore, in order to evaluate the role of the immune system in controlling the infection during latency, we induced immunosuppression in the infected monkeys. We first showed that the STLV-1 proviral load was higher in males than in females and increased significantly with the duration of infection: mandrills infected for 10–6 years had a significantly higher proviral load than those infected for 2–4 years. Curiously, this observation was associated with a clear reduction in CD4+ T-cell number with age. We also found that the percentage of CD4+ T cells co-expressing the activation marker HLA-DR and the mean percentage of CD25+ in CD4+ and CD8+ T cells were significantly higher in infected than in uninfected animals. Furthermore, the STLV-1 proviral load correlated positively with T-cell activation but not with the frequency of T cells secreting interferon γ in response to Tax peptides. Lastly, we showed that, during immunosuppression in infected monkeys, the percentages of CD8+ T cells expressing HLA-DR+ and of CD4+ T cells expressing the proliferation marker Ki67 decreased significantly, although the percentage of CD8+ T cells expressing HLA-DR+ and Ki67 increased significantly by the end of treatment. Interestingly, the proviral load increased significantly after immunosuppression in the monkey with the highest load. Our study demonstrates that mandrills naturally infected with STLV-1 could be a suitable model for studying the relations between host and virus. Further studies are needed to determine whether the different compartments of the immune response during infection induce the long latency by controlling viral replication over time. Such studies would provide important information for the development of immune-based therapeutic strategies.

本研究以自然感染猿T细胞白血病病毒1型（simian T-cell leukemia virus type 1, STLV-1）的山魈（Mandrillus sphinx）为模型，评估慢性感染阶段自然STLV-1感染对免疫系统动态与进化的影响。此外，为探究潜伏期内免疫系统在控制感染过程中的作用，我们对感染的山魈实施了免疫抑制处理。

我们首先证实，雄性个体的STLV-1前病毒负荷量高于雌性，且随感染时长显著升高：感染6~10年的山魈其前病毒负荷量显著高于感染2~4年的个体（原文为10–6年，疑为笔误，已按感染时长逻辑调整）。值得注意的是，这一观察结果与CD4阳性T细胞（CD4+ T-cell）数量随年龄增长显著降低的现象相关。

我们还发现，相较于未感染个体，感染个体中共表达激活标记物人类白细胞抗原DR（HLA-DR）的CD4阳性T细胞占比，以及CD4阳性、CD8阳性T细胞中CD25阳性细胞的平均占比均显著升高。进一步分析显示，STLV-1前病毒负荷量与T细胞激活程度呈正相关，但与响应Tax肽段（Tax peptides）分泌γ干扰素（interferon γ）的T细胞频率无明显关联。

最后，我们证实，在感染山魈接受免疫抑制处理期间，表达HLA-DR的CD8阳性T细胞占比、表达Ki67增殖标记物的CD4阳性T细胞占比均显著下降；但在处理结束时，同时表达HLA-DR与Ki67的CD8阳性T细胞占比显著升高。有趣的是，前病毒负荷量最高的受试山魈，其STLV-1前病毒负荷量在免疫抑制处理后显著上升。

本研究表明，自然感染STLV-1的山魈可作为研究宿主与病毒相互作用关系的适宜模型。未来仍需开展进一步研究，以明确感染过程中不同免疫应答亚群是否通过长期调控病毒复制，从而维持病毒的长潜伏期。此类研究将为基于免疫的治疗策略开发提供关键参考依据。