Wu Chengxiang, Johnson Nathan M, Yu Shan, Lo Agnes S, Sahu Gautam K, Marx Preston A, von Laer Dorothee, Skowron Gail, Geleziunas Romas, Shaw George M, Kaur Amitinder, Junghans Richard P, Braun Stephen E
Tulane National Primate Research Center, Tulane University School of Medicine, Covington, Louisiana, USA.
Department of Immunology, Tulane University School of Medicine, New Orleans, Louisiana, USA.
J Virol. 2025 May 20;99(5):e0193324. doi: 10.1128/jvi.01933-24. Epub 2025 Apr 10.
The success of chimeric antigen receptor (CAR)-T cell (Tc) immunotherapy in refractory B-cell acute lymphoblastic leukemia (B-ALL) suggests adaptation of this strategy toward HIV. Because cytomegalovirus (CMV) vaccine vectors generated Tc responses that controlled viral replication, these studies aim to genetically modify CMV-specific Tc with HIV-CAR2 vectors and link HIV immunotherapy to persistent CMV antigen stimulation. To mimic a clinical scenario, rhesus macaques were challenged with the CCR5-tropic simian/human immunodeficiency virus (SHIV-D) prior to antiretroviral therapy (ART). Autologous CMV-specific Tc were transduced with the control CEA-CAR2 or CD4-CAR2/maC46 vectors and reinfused. After stopping ART, the plasma viral load (PVL) in the control rebounded and was sustained above 1.7 × 10 copies/mL; PVL in CD4-CAR2-treated animals was delayed up to 6 weeks and 10-fold lower. The CD4 CAR-Tc frequency peaked at day 7 and was detected in lymphoid tissues at 6 weeks. Both CEA-CAR2 and CD4-CAR2 persisted in PBMCs for about 2 years, which indicates that the CMV-specific CAR Tc were maintained based on their CMV specificity. However, long-term PVL was stable in all animals. Thus, CMV-specific CAR-Tc were active initially, persisted long term, but failed to control viral replication.IMPORTANCEBecause of latent viral reservoirs and a dysfunctional immune response, HIV replication rebounds when antiretroviral therapy is interrupted. Therefore, cytomegalovirus (CMV)-specific Tc were genetically modified with anti-HIV CD4-CAR2 vectors to link the targeting of the HIV envelope to the persistent CMV immune response. In this clinical scenario with simian/human immunodeficiency virus (SHIV) challenge and antiretroviral therapy (ART) suppression, early activity of the CAR Tc delayed rebound in the rhesus macaque/SHIV challenge model. However, even with long-term persistence of CAR Tc in the blood, control of viral replication was not achieved. These data suggest that CAR Tc will require additional interventions to cure HIV infection.
嵌合抗原受体（CAR）-T细胞免疫疗法在难治性B细胞急性淋巴细胞白血病（B-ALL）中的成功促使人们将该策略应用于治疗HIV。由于巨细胞病毒（CMV）疫苗载体可引发控制病毒复制的T细胞反应，因此这些研究旨在用HIV-CAR2载体对CMV特异性T细胞进行基因改造，并将HIV免疫疗法与持续的CMV抗原刺激联系起来。为模拟临床情况，在抗逆转录病毒疗法（ART）之前，用CCR5嗜性猿猴/人类免疫缺陷病毒（SHIV-D）感染恒河猴。用对照CEA-CAR2或CD4-CAR2/maC46载体转导自体CMV特异性T细胞并回输。停止ART后，对照组的血浆病毒载量（PVL）反弹，并持续维持在1.7×10拷贝/mL以上；接受CD4-CAR2治疗的动物的PVL延迟长达6周，且低10倍。CD4 CAR-T细胞频率在第7天达到峰值，并在6周时在淋巴组织中检测到。CEA-CAR2和CD4-CAR2在PBMC中均持续约2年，这表明CMV特异性CAR T细胞基于其CMV特异性得以维持。然而，所有动物的长期PVL都保持稳定。因此，CMV特异性CAR-T细胞最初具有活性，可长期持续存在，但未能控制病毒复制。
重要性：由于存在潜伏病毒库和功能失调的免疫反应，抗逆转录病毒疗法中断时HIV复制会反弹。因此，用抗HIV CD4-CAR2载体对巨细胞病毒（CMV）特异性T细胞进行基因改造，以将HIV包膜的靶向作用与持续的CMV免疫反应联系起来。在这种猿猴/人类免疫缺陷病毒（SHIV）感染和抗逆转录病毒疗法（ART）抑制的临床情况下，CAR T细胞的早期活性在恒河猴/SHIV感染模型中延迟了反弹。然而，即使CAR T细胞在血液中长期持续存在，也未能实现对病毒复制的控制。这些数据表明，CAR T细胞需要额外的干预措施来治愈HIV感染。
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