Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA, United States.
Department of Medicine, University of California, San Francisco, San Francisco, CA, United States.
Front Immunol. 2024 Jun 24;15:1405348. doi: 10.3389/fimmu.2024.1405348. eCollection 2024.
Antiretroviral therapy (ART) for HIV-1 treatment has improved lifespan but requires lifelong adherence for people living with HIV (PLWH), highlighting the need for a cure. Evaluation of potential cure strategies requires analytic treatment interruption (ATI) with close monitoring of viral rebound. Predictive biomarkers for HIV-1 rebound and/or duration of control during ATI will facilitate these HIV cure trials while minimizing risks. Available evidence suggests that host immune, glycomic, lipid, and metabolic markers of inflammation may be associated with HIV-1 persistence in PLWH who are treated during chronic HIV-1 infection.
We conducted analysis of HIV controllers who could maintain low levels of plasma HIV-1 without ART in a phase 1b vesatolimod trial. Baseline and pre-ATI levels of immune, glycomic, lipidomic, and metabolomic markers were tested for association with ATI outcomes (time of HIV-1 rebound to 200 copies/mL and 1,000 copies/mL, duration of HIV-1 RNA ≤400 copies/mL and change in intact proviral HIV-1 DNA during ATI) using Spearman's correlation and Cox proportional hazards model.
Higher levels of CD69+CD8+ T-cells were consistently associated with shorter time to HIV-1 rebound at baseline and pre-ATI. With few exceptions, baseline fucosylated, non-galactosylated, non-sialylated, bisecting IgG N-glycans were associated with shorter time to HIV rebound and duration of control as with previous studies. Baseline plasma MPA and HPA binding glycans and non-galactosylated/non-sialylated glycans were associated with longer time to HIV rebound, while baseline multiply-galactosylated glycans and sialylated glycans, GNA-binding glycans, NPA-binding glycans, WGA-binding glycans, and bisecting GlcNAc glycans were associated with shorter time to HIV rebound and duration of control. Fourteen bioactive lipids had significant baseline associations with longer time to rebound and duration of control, and larger intact proviral HIV-1 DNA changes; additionally, three baseline bioactive lipids were associated with shorter time to first rebound and duration of control.
Consistent with studies in HIV non-controllers, proinflammatory glycans, lipids, and metabolites were generally associated with shorter duration of HIV-1 control. Notable differences were observed between HIV controllers vs. non-controllers in some specific markers. For the first time, exploratory biomarkers of ATI viral outcomes in HIV-controllers were investigated but require further validation.
抗逆转录病毒疗法（ART）用于治疗 HIV-1 可延长患者寿命，但 HIV 感染者（PLWH）需要终生服药，这突显了治愈的必要性。评估潜在的治愈策略需要进行分析性治疗中断（ATI），并密切监测病毒反弹。HIV-1 反弹和/或 ATI 期间控制的持续时间的预测生物标志物将有助于这些 HIV 治愈试验，同时将风险降到最低。现有证据表明，宿主免疫、糖组学、脂质组学和代谢组学的炎症标志物可能与接受慢性 HIV-1 感染治疗的 PLWH 中 HIV-1 的持续存在有关。
我们对 1b 期 vesatolimod 试验中无需 ART 即可维持低水平血浆 HIV-1 的 HIV 控制者进行了分析。使用 Spearman 相关性和 Cox 比例风险模型，检测免疫、糖组学、脂质组学和代谢组学标志物的基线和 ATI 前水平与 ATI 结果（HIV-1 反弹至 200 拷贝/ml 和 1000 拷贝/ml 的时间、HIV-1 RNA ≤400 拷贝/ml 的持续时间和 ATI 期间完整前病毒 HIV-1 DNA 的变化）之间的关联。
CD69+CD8+T 细胞水平较高与基线和 ATI 前 HIV-1 反弹时间较短有关。除少数例外情况外，与之前的研究一样，基线上的岩藻糖基化、非半乳糖基化、非唾液酸化、双分叉 IgG N-糖与 HIV 反弹时间较短和控制时间较长有关。基线血浆 MPA 和 HPA 结合糖和非半乳糖基化/非唾液酸化糖与 HIV 反弹时间较长有关，而基线上多半乳糖基化糖和唾液酸化糖、GNA 结合糖、NPA 结合糖、WGA 结合糖和双分叉 GlcNAc 糖与 HIV 反弹时间较短和控制时间较长有关。14 种生物活性脂质与更长的反弹时间和更长的控制时间以及更大的完整前病毒 HIV-1 DNA 变化有关，此外，三种基线生物活性脂质与第一次反弹时间和控制时间较短有关。
与 HIV 非控制者的研究一致，促炎糖、脂质和代谢物通常与 HIV-1 控制时间较短有关。在某些特定标志物中，HIV 控制者与非控制者之间存在显著差异。这是首次对 HIV 控制者的 ATI 病毒结果的探索性生物标志物进行了研究，但需要进一步验证。
