Wu Fengting, Moskovljevic Milica, Dragoni Filippo, Jayaraman Sahana, Board Nathan L, Camilo-Contreras Angelica, Bernal Silvia, Hariharan Vivek, Zhang Hao, Lai Jun, Singhal Anushka, Poulin Sebastien, Chano Frederic, Chamberland Annie, Tremblay Cecile, Zoltick Meredith, Hoffmann Christopher J, Jones Joyce L, Larman H Benjamin, Montaner Luis J, Siliciano Janet D, Siliciano Robert F, Simonetti Francesco R
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Institute of Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins University, Baltimore, MD 21205, USA.
Sci Transl Med. 2025 Aug 13;17(811):eadu4643. doi: 10.1126/scitranslmed.adu4643.
Antiretroviral therapy (ART) halts human immunodeficiency virus-1 (HIV-1) replication, reducing plasma virus concentrations to below the limit of detection, but it is not curative because of a reservoir of latently infected CD4 T cells. In some people living with HIV-1 (PLWH), plasma HIV-1 RNA becomes persistently detectable despite optimal ART. This nonsuppressible viremia (NSV) is characterized by identical, nonevolving HIV-1 RNA variants expressed from infected CD4 T cell clones. The mechanisms driving persistent virus production from a specific population of infected cells are poorly understood. We hypothesized that proviruses in cells responding to chronic immunologic stimuli, including self-associated antigens, may drive viral gene expression and NSV. Here, we demonstrate that stimulation of CD4 T cells with autologous cell lysates induced virus production in a major histocompatibility complex class II-dependent manner. In seven of eight participants with NSV, we recovered viral RNA released ex vivo in response to autologous cell lysates that matched plasma virus. This process involved both defective and replication-competent proviruses residing in conventional CD4 T cells and was also observed in PLWH with undetectable viremia. These findings suggest that recognition of self-associated antigens is a potentially important cause of HIV-1 reservoir expression, which can contribute to persistent systemic inflammation and rebound upon ART interruption.
抗逆转录病毒疗法（ART）可阻止人类免疫缺陷病毒1型（HIV-1）复制，将血浆病毒浓度降低至检测下限以下，但由于存在潜伏感染的CD4 T细胞库，该疗法无法治愈。在一些HIV-1感染者（PLWH）中，尽管接受了最佳的ART治疗，血浆HIV-1 RNA仍可持续检测到。这种不可抑制的病毒血症（NSV）的特征是由受感染的CD4 T细胞克隆表达的相同、不进化的HIV-1 RNA变体。驱动特定感染细胞群体持续产生病毒的机制尚不清楚。我们假设，对包括自身相关抗原在内的慢性免疫刺激作出反应的细胞中的前病毒可能驱动病毒基因表达和NSV。在这里，我们证明用自体细胞裂解物刺激CD4 T细胞以主要组织相容性复合体II类依赖的方式诱导病毒产生。在八名NSV参与者中的七名中，我们回收了离体释放的病毒RNA，其对与血浆病毒匹配的自体细胞裂解物有反应。这一过程涉及存在于传统CD4 T细胞中的有缺陷和具有复制能力的前病毒，在病毒血症无法检测到的PLWH中也观察到了这一现象。这些发现表明，对自身相关抗原的识别是HIV-1储存库表达的一个潜在重要原因，这可能导致持续的全身炎症和ART中断后的病毒反弹。
