HIV-specific T cell responses reflect substantive in vivo interactions with antigen despite long-term therapy
HIV-specific T cell responses reflect substantive in vivo interactions with antigen despite long-term therapy
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DOI：
10.1172/jci.insight.142640
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发表时间：
2021-02-08
期刊：
影响因子：
8
通讯作者：
Jones, R. Brad
中科院分区：
文献类型：
--
作者：
Stevenson, Eva M.;Ward, Adam R.;Jones, R. Brad
抗逆转录病毒疗法（ART）消除艾滋病毒复制;然而，感染持续存在，因为感染细胞与整合的前病毒，如果ART中断，重新播种复制的长寿水库。我们目前对这种持久性的理解的一个中心原则是，受感染的细胞通过缺乏来自前病毒的抗原表达而免受免疫识别和消除。因此，治疗HIV感染的努力集中在重新激活潜伏的前病毒以使免疫介导的清除成为可能，但这些尚未成功减少病毒储库。在这里，我们从一个新的角度重新审视了HIV储库是否主要是免疫沉默的问题：通过查询长期ART中HIV特异性T细胞应答的动态，以获得持续识别HIV感染细胞的证据。在纵向评估中，我们发现持续的HIV Nef特异性反应的变化率，而不是对其他HIV基因产物的反应，与感染细胞的残留频率相关。这些Nef特异性应答随时间高度稳定，并且不成比例地表现出细胞毒性效应子功能特征，表明最近体内识别HIV抗原。这些结果表明，HIV感染的细胞对稳定ART的T细胞的可见性很高，为开发治疗感染的治疗方法提供了机遇和挑战。
Antiretroviral therapies (ARTs) abrogate HIV replication; however, infection persists as long-lived reservoirs of infected cells with integrated proviruses, which reseed replication if ART is interrupted. A central tenet of our current understanding of this persistence is that infected cells are shielded from immune recognition and elimination through a lack of antigen expression from proviruses. Efforts to cure HIV infection have therefore focused on reactivating latent proviruses to enable immune-mediated clearance, but these have yet to succeed in reducing viral reservoirs. Here, we revisited the question of whether HIV reservoirs are predominately immunologically silent from a new angle: by querying the dynamics of HIV-specific T cell responses over long-term ART for evidence of ongoing recognition of HIV-infected cells. In longitudinal assessments, we show that the rates of change in persisting HIV Nef-specific responses, but not responses to other HIV gene products, were associated with residual frequencies of infected cells. These Nef- specific responses were highly stable over time and disproportionately exhibited a cytotoxic, effector functional profile, indicative of recent in vivo recognition of HIV antigens. These results indicate substantial visibility of the HIV-infected cells to T cells on stable ART, presenting both opportunities and challenges for the development of therapeutic approaches to curing infection.