Chronic HIV infection accelerates immune aging and is associated with abnormal hemato-lymphopoiesis, but the relationship between HIV-induced aging and Hematopoietic Progenitor Cells (HPC) function is not well-defined. In the context of aging, it has been demonstrated using a murine model that Per2 (Period circadian clock 2) is a negative regulator of HPC survival and lineage potential. A possible involvement of Per2 modulation on hematopoietic failure during HIV infection has not yet been investigated. The aim of this study was to analyze whether Per2 is differently expressed and regulated on HPC during HIV infection, possibly providing a therapeutic target to restore lymphoid potential in the HPC compartment. To this purpose, Per2 expression in circulating HPC was compared in 69 chronic HIV infected patients under successful ART and in matched 30 uninfected healthy donors (HD). HPC aging was assessed by measuring relative telomere length (RTL), and HPC functionality was evaluated by Colony Forming Cell (CFC) assay from both ex vivo HIV+ patients and in vitro Per2 overexpressing donors. Our results showed a lower RTL in HPC and a decrease of white progenitor colonies from HIV+ patients with lower CD4 respect to those with higher CD4 T cell count (<500 respect to >500 CD4 T cell/mmc). Interestingly, we found that the frequency of Per2-expressing HPC is higher in HIV+ patients than in HD and correlated to RTL of CFC derived cells, highlighting a relationship between low proliferative rate and Per2 expression. Indeed, the in vitro overexpression of Per2 resulted in a significant decrease of white progenitor colonies respect to control cells. Finally, we showed that the deacetylase Sirtuin 1, a negative regulator of Per2, was downregulated in HPC from HIV+ patients, and the peripheral blood treatment with resveratrol (Sirtuin 1 inducer) determined a decrease of Per2 expressing HPC. Altogether, these results suggest that during HIV infection, Per2 is involved in the regulation of HPC expansion and differentiation and its overexpression may impair the immune reconstitution. These data support the rationale to explore the role of this regulatory mechanism during aged-associated hemato-lymphopoiesis impairment in HIV infection.

慢性 HIV 感染会加速免疫衰老，并与异常的造血淋巴细胞生成有关，但 HIV 诱导的衰老与造血祖细胞 (HPC) 功能之间的关系尚不明确。在衰老的背景下，已经使用鼠模型证明 Per2（周期生物钟 2）是 HPC 存活和谱系潜力的负调节剂。尚未研究 Per2 调节对 HIV 感染期间造血衰竭的可能参与。本研究的目的是分析在 HIV 感染期间 Per2 在 HPC 上是否有不同的表达和调节，可能为恢复 HPC 隔室的淋巴潜能提供治疗靶点。为此，在成功进行 ART 的 69 名慢性 HIV 感染患者和匹配的 30 名未感染健康供体 (HD) 中比较了循环 HPC 中 Per2 的表达。通过测量相对端粒长度 (RTL) 评估 HPC 老化，并通过集落形成细胞 (CFC) 测定从两者评估 HPC 功能离体HIV+ 患者和体外Per2 过度表达供体。我们的结果显示，与 CD4 T 细胞计数较高的患者相比，HPC 中的 RTL 较低，并且 CD4 较低的 HIV+ 患者的白色祖细胞集落减少（<500 相对于 >500 CD4 T 细胞/mmc）。有趣的是，我们发现在 HIV+ 患者中表达 Per2 的 HPC 的频率高于在 HD 中，并且与 CFC 衍生细胞的 RTL 相关，突出了低增殖率与 Per2 表达之间的关系。的确，体外Per2 的过表达导致白色祖细胞集落相对于对照细胞显着减少。最后，我们发现去乙酰化酶 Sirtuin 1（一种 Per2 的负调节剂）在 HIV+ 患者的 HPC 中下调，并且用白藜芦醇（Sirtuin 1 诱导剂）进行的外周血治疗确定了表达 Per2 的 HPC 的减少。总之，这些结果表明，在 HIV 感染期间，Per2 参与了 HPC 扩增和分化的调节，其过表达可能会损害免疫重建。这些数据支持探索这种调节机制在 HIV 感染中与老年相关的造血淋巴细胞损伤中的作用的基本原理。