Buchholtz Ninée V E J, Hermans Lucas E, Umunnakwe Chijioke N, Nühn Marieke M, Voss Regina, Need Emma, Kootstra Neeltje A, Maurer Irma, de Jong Dorien C M, Symons Jori, Tempelman Hugo A, Wensing Annemarie M J, Nijhuis Monique
Translational Virology, Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, Netherlands.
Ndlovu Laboratories, Ndlovu Research Center, Ndlovu Academic Department, Ndlovu Care Group, Elandsdoorn, South Africa.
Front Immunol. 2024 Nov 26;15:1484358. doi: 10.3389/fimmu.2024.1484358. eCollection 2024.
The main obstacle to achieving an HIV-1 cure is the proviral reservoir. To promote equity in HIV cure strategies, it is crucial to study the viral reservoir of the predominant HIV-1 subtype C in both women and men. Therefore, we investigated the dynamics of the (intact) viral reservoir in relation to plasma viral load (VL), CD4 T cell count, and immune activation before and during 96 weeks of successful antiretroviral therapy (ART).
Eighty-two participants (62% female) newly initiating ART in a rural clinic in South Africa were included in the study. Blood samples were collected at baseline, week 48, and week 96, and CD4 count was determined. Plasma was used for VL and immune marker analyses, while isolated peripheral blood mononuclear cells (PBMCs) were used for the quantification of cellular multiple spliced HIV-1 RNA (msRNA) and the intact proviral DNA assay. For the longitudinal analyses on ART, we selected only those participants who durably suppressed their VL to <200 copies/mL during 48 (n=65) and/or 96 (n=60) weeks of treatment.
At ART initiation, the median CD4 count was 234 cells/mm3 and VL was 68,897 copies/mL. Interestingly, at baseline the number of defective proviruses was significantly correlated with VL (p<0.0001), msRNA (p<0.0001), CD4 count (p=0.0008), CXCL10 (p=0.0003) and TNF-α (p=0.0394). During successful ART, a significant decrease of both the intact and defective proviral reservoir was observed (p<0.0001). The decrease of the intact proviral reservoir was more profound compared to the defective fraction after 96 weeks of therapy. In addition, a significant decrease in cellular msRNA and IL-6, IL-7, TNF-α, sCD14, sCD163, CCL2, CXCL10, and CRP was detected.
This study underscores the significant relationship observed prior to therapy initiation between the number of defective proviruses, viral transcription/production and their association with immune response indicators such as CD4 count, CXCL10, and TNF-α. Furthermore, the observation of a less pronounced decrease of the defective proviral DNA highlights the importance of addressing both intact and defective proviruses in therapeutic strategies to enhance clinical outcomes for people with HIV-1. Together, these findings suggest a significant role of the defective proviruses in HIV-related disease progression.
实现治愈人类免疫缺陷病毒1型（HIV-1）的主要障碍是前病毒储存库。为促进HIV治愈策略的公平性，研究男女中主要HIV-1 C亚型的病毒储存库至关重要。因此，我们调查了在96周成功抗逆转录病毒治疗（ART）之前及期间完整病毒储存库与血浆病毒载量（VL）、CD4 T细胞计数和免疫激活之间的动态关系。
本研究纳入了在南非一家农村诊所新开始接受ART治疗的82名参与者（62%为女性）。在基线、第48周和第96周采集血样并测定CD4计数。血浆用于VL和免疫标志物分析，而分离的外周血单核细胞（PBMC）用于定量细胞内多重剪接HIV-1 RNA（msRNA）和完整前病毒DNA检测。对于ART的纵向分析，我们仅选择那些在48周（n = 65）和/或96周（n = 60）治疗期间将VL持续抑制至<200拷贝/mL的参与者。
开始ART治疗时，CD4计数中位数为234个细胞/mm³，VL为68,897拷贝/mL。有趣的是，在基线时，缺陷前病毒的数量与VL（p<0.0001）、msRNA（p<0.0001）、CD4计数（p = 0.0008）、CXCL10（p = 0.0003）和TNF-α（p = 0.0394）显著相关。在成功的ART治疗期间，观察到完整和缺陷前病毒储存库均显著减少（p<0.0001）。治疗96周后，完整前病毒储存库的减少比缺陷部分更为显著。此外，还检测到细胞内msRNA以及IL-6、IL-7、TNF-α、sCD14、sCDl63、CCL2、CXCL10和CRP显著减少。
本研究强调了在治疗开始前观察到的缺陷前病毒数量、病毒转录/产生及其与免疫反应指标（如CD4计数）、CXCL10和TNF-α之间的显著关系。此外，缺陷前病毒DNA减少不太明显的观察结果突出了在治疗策略中同时解决完整和缺陷前病毒以改善HIV-1感染者临床结局的重要性。总之，这些发现表明缺陷前病毒在HIV相关疾病进展中起重要作用。
