Division of Infectious Disease, Department of Medicine, University of Arizona, Tucson, AZ, United States.
Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN, United States.
Front Immunol. 2018 Jan 25;9:20. doi: 10.3389/fimmu.2018.00020. eCollection 2018.
The majority of HIV replication occurs in secondary lymphoid organs (SLOs) such as the spleen, lymph nodes, and gut-associated lymphoid tissue. Within SLOs, HIV RNA cells are concentrated in the B-cell follicle during chronic untreated infection, and emerging data suggest that they are a major source of replication in treated disease as well. The concentration of HIV RNA cells in the B-cell follicle is mediated by several factors. Follicular CD4 T-cell subsets including T-follicular helper cells and T-follicular regulatory cells are significantly more permissive to HIV than extrafollicular subsets. The B cell follicle also contains a large reservoir of extracellular HIV virions, which accumulate on the surface of follicular dendritic cells (FDCs) in germinal centers. FDC-bound HIV virions remain infectious even in the presence of neutralizing antibodies and can persist for months or even years. Moreover, the B-cell follicle is semi-immune privileged from CTL control. Frequencies of HIV- and SIV-specific CTL are lower in B-cell follicles compared to extrafollicular regions as the majority of CTL do not express the follicular homing receptor CXCR5. Additionally, CTL in the B-cell follicle may be less functional than extrafollicular CTL as many exhibit the recently described CD8 T follicular regulatory phenotype. Other factors may also contribute to the follicular concentration of HIV RNA cells. Notably, the contribution of NK cells and γδ T cells to control and/or persistence of HIV RNA cells in secondary lymphoid tissue remains poorly characterized. As HIV research moves increasingly toward the development of cure strategies, a greater understanding of the barriers to control of HIV infection in B-cell follicles is critical. Although no strategy has as of yet proven to be effective, a range of novel therapies to address these barriers are currently being investigated including genetically engineered CTL or chimeric antigen receptor T cells that express the follicular homing molecule CXCR5, treatment with IL-15 or an IL-15 superagonist, use of bispecific antibodies to harness the killing power of the follicular CD8 T cell population, and disruption of the follicle through treatments such as rituximab.
大多数 HIV 复制发生在次级淋巴器官 (SLO) 中，如脾脏、淋巴结和肠道相关淋巴组织。在 SLO 中，慢性未经治疗的感染中，HIV RNA 细胞集中在 B 细胞滤泡中，新出现的数据表明，它们也是治疗疾病中复制的主要来源。HIV RNA 细胞在 B 细胞滤泡中的浓缩是由几种因素介导的。滤泡性 CD4 T 细胞亚群，包括滤泡辅助性 T 细胞和滤泡调节性 T 细胞，比滤泡外亚群对 HIV 的允许性更高。滤泡性 CD4 T 细胞亚群，包括滤泡辅助性 T 细胞和滤泡调节性 T 细胞，比滤泡外亚群对 HIV 的允许性更高。滤泡性 CD4 T 细胞亚群，包括滤泡辅助性 T 细胞和滤泡调节性 T 细胞，比滤泡外亚群对 HIV 的允许性更高。B 细胞滤泡还含有大量的细胞外 HIV 病毒粒子，这些病毒粒子在生发中心的滤泡树突状细胞 (FDC) 表面积累。即使存在中和抗体，FDC 结合的 HIV 病毒粒子仍然具有感染性，并可持续数月甚至数年。此外，B 细胞滤泡对 CTL 控制具有半免疫特权。与滤泡外区域相比，HIV 和 SIV 特异性 CTL 的频率在 B 细胞滤泡中较低，因为大多数 CTL 不表达滤泡归巢受体 CXCR5。此外，B 细胞滤泡中的 CTL 可能不如滤泡外 CTL 功能强大，因为许多 CTL 表现出最近描述的 CD8 T 滤泡调节表型。其他因素也可能导致 HIV RNA 细胞在滤泡中的浓缩。值得注意的是，NK 细胞和 γδ T 细胞对 SLO 中 HIV RNA 细胞的控制和/或持续存在的贡献仍未得到充分描述。随着 HIV 研究越来越倾向于开发治愈策略，对控制 B 细胞滤泡中 HIV 感染的障碍有更深入的了解至关重要。尽管目前还没有一种策略被证明是有效的，但目前正在研究一系列新的治疗方法来解决这些障碍，包括表达滤泡归巢分子 CXCR5 的基因工程 CTL 或嵌合抗原受体 T 细胞、用 IL-15 或 IL-15 超激动剂治疗、使用双特异性抗体利用滤泡 CD8 T 细胞群体的杀伤能力，以及通过利妥昔单抗等治疗方法破坏滤泡。
