Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.
Ragon Institute of Massachusetts General Hospital, MIT, and Harvard, Cambridge, MA, United States.
Front Immunol. 2019 Aug 14;10:1850. doi: 10.3389/fimmu.2019.01850. eCollection 2019.
Despite efficient suppression of plasma viremia in people living with HIV (PLWH) on cART, evidence of HIV-induced immunosuppression remains, and normally benign and opportunistic pathogens become major sources of co-morbidities, including virus-induced cancers. In fact, cancer remains a primary cause of death even in virally suppressed PLWH. Natural killer (NK) cells provide rapid early responses to HIV infection, contribute substantially to disease modulation and vaccine protection, and are also major therapeutic targets for cancer immunotherapy. However, much like other lymphocyte populations, recent burgeoning evidence suggests that in chronic conditions like HIV, NK cells can become functionally exhausted with impaired cytotoxic function, altered cytokine production and impaired antibody-dependent cell-mediated cytotoxicity. Recent work suggests functional anergy is likely due to low-level ongoing virus replication, increased inflammatory cytokines, or increased presence of MHC target cells. Indeed, HIV-induced loss of NK cell-mediated control of lytic EBV infection has been specifically shown to cause lymphoma and also increases replication of CMV. In this review, we will discuss current understanding of NK cell modulation of HIV disease, reciprocal exhaustion of NK cells, and how this may impact increased cancer incidences and prospects for NK cell-targeted immunotherapies. Finally, we will review the most recent evidence supporting adaptive functions of NK cells and highlight the potential of adaptive NK cells for cancer immunotherapy.
尽管接受抗逆转录病毒疗法 (cART) 的艾滋病毒感染者 (PLWH) 的血浆病毒血症得到有效抑制，但仍存在 HIV 引起的免疫抑制证据，通常良性和机会性病原体成为合并症的主要来源，包括病毒诱导的癌症。事实上，即使在病毒得到抑制的 PLWH 中，癌症仍然是主要的死亡原因。自然杀伤 (NK) 细胞对 HIV 感染提供快速的早期反应，对疾病调节和疫苗保护做出重大贡献，也是癌症免疫治疗的主要治疗靶点。然而，就像其他淋巴细胞群一样，最近涌现的大量证据表明，在像 HIV 这样的慢性疾病中，NK 细胞可能会因低水平的持续病毒复制、增加的炎症细胞因子或增加的 MHC 靶细胞而出现功能衰竭，导致细胞毒性功能受损、细胞因子产生改变和抗体依赖性细胞介导的细胞毒性受损。最近的研究表明，功能失能可能是由于低水平的持续病毒复制、炎症细胞因子增加，或 MHC 靶细胞增加。事实上，已经有研究表明，HIV 诱导的 NK 细胞对裂解性 EBV 感染的控制丧失会导致淋巴瘤，并增加 CMV 的复制。在这篇综述中，我们将讨论当前对 NK 细胞调节 HIV 疾病、NK 细胞相互耗竭的理解，以及这如何影响癌症发病率的增加和 NK 细胞靶向免疫治疗的前景。最后，我们将回顾支持 NK 细胞适应性功能的最新证据，并强调适应性 NK 细胞在癌症免疫治疗中的潜力。
