Infectious Diseases Clinic, IRCCS Policlinico San Martino Hospital, Genoa, Italy.
Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy.
Front Immunol. 2022 Apr 26;13:847816. doi: 10.3389/fimmu.2022.847816. eCollection 2022.
The quantification of proviral DNA is raising interest in view of clinical management and functional HIV eradication. Measures of all unintegrated HIV DNA (uDNA) forms in infected reservoir cells provides information on recent replication events that is not found from other proviral DNA assays. To evaluate its actual relevance in a cohort of perinatally-infected adult HIV patients (PHIV), we studied how peripheral blood mononuclear cell uDNA levels correlated with total HIV DNA (tDNA) and with overall replication or innate immune control parameters including NK cell activation/exhaustion and lymphoid turnover. Twenty-two PHIV were included, with successfully controlled HIV (HIV RNA <50 copies/mL) on combined antiretroviral therapy for mean of 8.7 ± 3.9 years. uDNA accounted for 16 [5.2-83.5] copies/µg and was strongly correlated with tDNA (ρ=0.700, p=0.001). Flow cytometric analysis of peripheral NK cells showed that CD69 expression was directly correlated uDNA (p=0.0412), but not with tDNA. Interestingly, CD56CD16NK cells which include newly described inflammatory precursors and terminally differentiated cells were directly correlated with uDNA levels (p<0.001), but not with tDNA, and an inverse association was observed between the proportion of NKG2D NK cells and uDNA (ρ=-0.548, p=0.015). In addition, CD34DNAM-1CXCR4 inflammatory precursor frequency correlated directly with uDNA levels (ρ=0.579, p=0.0075). The frequencies of CD56CD16 and CD34DNAM-1CXCR4 cells maintained association with uDNA levels in a multivariable analysis (p=0.045 and p=0.168, respectively). Thus, control of HIV-1 reservoir in aviremic patients on ART is an active process associated with continuous NK cell intervention and turnover, even after many years of treatment. Quantification of linear and circular uDNA provides relevant information on the requirement for ongoing innate immune control in addition to ART, on recent replication history and may help stratify patients for functional HIV eradication protocols with targeted options.
病毒前 DNA 的定量分析引起了人们的兴趣，因为它与临床管理和功能性 HIV 清除有关。测量感染储库细胞中的所有未整合 HIV DNA（uDNA）形式，可以提供有关最近复制事件的信息，而这些信息无法从其他前病毒 DNA 检测中获得。为了评估其在一组围产期感染的成年 HIV 患者（PHIV）中的实际相关性，我们研究了外周血单核细胞 uDNA 水平与总 HIV DNA（tDNA）以及整体复制或固有免疫控制参数（包括 NK 细胞激活/耗竭和淋巴细胞更新）之间的相关性。纳入了 22 名 PHIV，他们在接受联合抗逆转录病毒治疗（ART）后 HIV RNA <50 拷贝/mL，平均 8.7 ± 3.9 年。uDNA 占 16 [5.2-83.5]拷贝/μg，与 tDNA 呈强相关性（ρ=0.700，p=0.001）。外周 NK 细胞的流式细胞术分析表明，CD69 表达与 uDNA 直接相关（p=0.0412），但与 tDNA 无关。有趣的是，包括新描述的炎症前体和终末分化细胞的 CD56CD16NK 细胞与 uDNA 水平直接相关（p<0.001），但与 tDNA 无关，NKG2D NK 细胞的比例与 uDNA 呈负相关（ρ=-0.548，p=0.015）。此外，CD34DNAM-1CXCR4 炎症前体频率与 uDNA 水平直接相关（ρ=0.579，p=0.0075）。在多变量分析中，CD56CD16 和 CD34DNAM-1CXCR4 细胞的频率与 uDNA 水平保持关联（p=0.045 和 p=0.168）。因此，在接受 ART 的无病毒血症患者中，HIV-1 储库的控制是一个活跃的过程，与持续的 NK 细胞干预和更新有关，即使在经过多年的治疗后也是如此。线性和环状 uDNA 的定量分析提供了有关在 ART 之外持续进行固有免疫控制、最近复制史的相关信息，并可能有助于为具有靶向选择的功能性 HIV 清除协议分层患者。
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