Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institute of Health, Bethesda, MD, USA.
Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institute of Health, Bethesda, MD, USA.
EBioMedicine. 2024 Jun;104:105151. doi: 10.1016/j.ebiom.2024.105151. Epub 2024 May 9.
People living with HIV (PLWH) with multidrug-resistant (MDR) viruses have limited therapeutic options and present challenges regarding clinical management. Recent studies have shown that passive transfer of combination broadly neutralizing antibodies (bNAbs) against HIV and anti-domain 1 CD4 antibody UB-421 can sustain virologic suppression in PLWH in the absence of antiretroviral therapy (ART). Yet studies addressing the therapeutic potential of these antibodies and/or detailed characterization of immunologic and virologic parameters in PLWH with MDR HIV are lacking.
We examined levels of immune activation and exhaustion markers on CD8 T cells and the intact HIV proviral DNA burden in 11 PLWH with MDR viruses. For comparison purposes, we included a control group consisting of 27 ART-naïve viremic PLWH. In addition, we determined the sensitivity of infectious viral isolates obtained from the participants against eight bNAbs (3BNC117, 10-1074, VRC01, VRC07, N6, 10E8, PGDM1400, and PGT121) and two anti-CD4 antibodies (ibalizumab and UB-421) using a TZM-bl-based neutralization/suppression assay.
The level of intact HIV proviral DNA was comparable between the two groups (P = 0.29). The levels of activation and exhaustion markers PD-1 (P = 0.0019), TIGIT (P = 0.0222), 2B4 (P = 0.0015), CD160 (P = 0.0015), and CD38/HLA-DR (P = 0.0138) were significantly lower in the MDR group. The infectious viral isolates from each study participant with MDR HIV were resistant to at least 2 bNAbs; however, they were sensitive to at least one of the CD4-binding and non-CD4-binding site antibodies. The majority of participants had ibalizumab-sensitive viruses although the isolates from some participants showed reduced sensitivity to ibalizumab. Notably, none of the 93 viral isolates obtained from the participants were resistant to UB-421.
Our data suggest that combination therapy with HIV-specific bNAbs and/or UB-421 in the presence of optimized background therapy could potentially provide sustained virologic suppression in PLWH with MDR HIV. However, this therapeutic strategy needs to be evaluated in human clinical trials.
Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.
携带多药耐药（MDR）病毒的 HIV 感染者（PLWH）治疗选择有限，临床管理存在挑战。最近的研究表明，针对 HIV 的组合广泛中和抗体（bNAb）和抗域 1 CD4 抗体 UB-421 的被动转移可以在没有抗逆转录病毒治疗（ART）的情况下维持 PLWH 的病毒学抑制。然而，关于这些抗体的治疗潜力以及 MDR HIV 感染者免疫和病毒学参数的详细特征的研究尚缺乏。
我们检测了 11 例携带 MDR 病毒的 PLWH 中 CD8 T 细胞的免疫激活和耗竭标志物以及完整 HIV 前病毒 DNA 负担。为了比较目的，我们纳入了由 27 例未经 ART 治疗的病毒血症 PLWH 组成的对照组。此外，我们使用基于 TZM-bl 的中和/抑制测定法，确定了从参与者中获得的感染性病毒分离物对八种 bNAb（3BNC117、10-1074、VRC01、VRC07、N6、10E8、PGDM1400 和 PGT121）和两种抗 CD4 抗体（ibalizumab 和 UB-421）的敏感性。
两组之间完整 HIV 前病毒 DNA 水平相当（P=0.29）。MDR 组的激活和耗竭标志物 PD-1（P=0.0019）、TIGIT（P=0.0222）、2B4（P=0.0015）、CD160（P=0.0015）和 CD38/HLA-DR（P=0.0138）水平明显较低。每位 MDR HIV 参与者的感染性病毒分离物对至少两种 bNAb 具有耐药性；然而，它们对至少一种 CD4 结合和非 CD4 结合位点抗体敏感。大多数参与者的病毒对ibalizumab 敏感，尽管一些参与者的分离物对ibalizumab 的敏感性降低。值得注意的是，从参与者中获得的 93 个病毒分离物中没有一个对 UB-421 耐药。
我们的数据表明，在优化背景治疗的基础上，联合使用 HIV 特异性 bNAb 和/或 UB-421 治疗可能为 MDR HIV 的 PLWH 提供持续的病毒学抑制。然而，这种治疗策略需要在人体临床试验中进行评估。
国家过敏和传染病研究所，国立卫生研究院，内部研究部门。
