Ribeiro Susan P, Milush Jeffrey M, Cunha-Neto Edecio, Kallas Esper G, Kalil Jorge, Somsouk Ma, Hunt Peter W, Deeks Steven G, Nixon Douglas F, SenGupta Devi
Laboratory of Clinical Immunology and Allergy-LIM60, University of São Paulo School of Medicine, São Paulo, Brazil Institute of Investigation in Immunology-iii-INCT, São Paulo, Brazil.
Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
J Virol. 2014 Dec;88(23):13836-44. doi: 10.1128/JVI.01948-14. Epub 2014 Sep 24.
Memory stem T cells (T(SCM)) constitute a long-lived, self-renewing lymphocyte population essential for the maintenance of functional immunity. The hallmarks of HIV-1 pathogenesis are CD4(+) T cell depletion and abnormal cellular activation. We investigated the impact of HIV-1 infection on the T(SCM) compartment, as well as any protective role these cells may have in disease progression, by characterizing this subset in a cohort of 113 subjects with various degrees of viral control on and off highly active antiretroviral therapy (HAART). We observed that the frequency of CD8(+) T(SCM) was decreased in all individuals with chronic, untreated HIV-1 infection and that HAART had a restorative effect on this subset. In contrast, natural controllers of HIV-1 had the highest absolute number of CD4(+) T(SCM) cells among all of the infected groups. The frequency of CD4(+) T(SCM) predicted higher CD8(+) T(SCM) frequencies, consistent with a role for the CD4(+) subset in helping to maintain CD8(+) memory T cells. In addition, T(SCM) appeared to be progenitors for effector T cells (TEM), as these two compartments were inversely correlated. Increased frequencies of CD8(+) T(SCM) predicted lower viral loads, higher CD4(+) counts, and less CD8(+) T cell activation. Finally, we found that T(SCM) express the mucosal homing integrin α4β7 and can be identified in gut-associated lymphoid tissue (GALT). The frequency of mucosal CD4(+) T(SCM) was inversely correlated with that in the blood, potentially reflecting the ability of these self-renewing cells to migrate to a crucial site of ongoing viral replication and CD4(+) T cell depletion.
HIV-1 infection leads to profound impairment of the immune system. T(SCM) constitute a recently identified lymphocyte subset with stem cell-like qualities, including the ability to generate other memory T cell subtypes, and are therefore likely to play an important role in controlling viral infection. We investigated the relationship between the size of the CD8(+) T(SCM) compartment and HIV-1 disease progression in a cohort of chronically infected individuals. Our results suggest that HAART restores a normal frequency of CD8(+) T(SCM) and that the natural preservation of this subset in the setting of untreated HIV-1 infection is associated with improved viral control and immunity. Therefore, the CD8(+) T(SCM) population may represent a correlate of protection in chronic HIV-1 infection that is directly relevant to the design of T cell-based vaccines, adoptive immunotherapy approaches, or the pharmacologic induction of T(SCM).
记忆性干细胞样T细胞（T(SCM)）构成了一个长寿、自我更新的淋巴细胞群体，对维持功能性免疫至关重要。HIV-1发病机制的标志是CD4(+) T细胞耗竭和细胞异常激活。我们通过对113名在接受和未接受高效抗逆转录病毒治疗（HAART）情况下具有不同程度病毒控制水平的受试者队列中的这一亚群进行特征分析，研究了HIV-1感染对T(SCM)区室的影响，以及这些细胞在疾病进展中可能具有的任何保护作用。我们观察到，在所有慢性未治疗的HIV-1感染者中，CD8(+) T(SCM)的频率均降低，且HAART对该亚群具有恢复作用。相比之下，HIV-1自然控制者在所有感染组中CD4(+) T(SCM)细胞的绝对数量最高。CD4(+) T(SCM)的频率预示着更高的CD8(+) T(SCM)频率，这与CD4(+)亚群在帮助维持CD8(+)记忆T细胞方面的作用一致。此外，T(SCM)似乎是效应T细胞（TEM）的祖细胞，因为这两个区室呈负相关。CD8(+) T(SCM)频率增加预示着病毒载量降低、CD4(+)细胞计数升高以及CD8(+) T细胞激活减少。最后，我们发现T(SCM)表达黏膜归巢整合素α4β7，并且可以在肠道相关淋巴组织（GALT）中被识别。黏膜CD4(+) T(SCM)的频率与血液中的频率呈负相关，这可能反映了这些自我更新细胞迁移到正在进行病毒复制和CD4(+) T细胞耗竭的关键部位的能力。
HIV-1感染导致免疫系统严重受损。T(SCM)构成了最近鉴定出的具有干细胞样特性的淋巴细胞亚群，包括产生其他记忆T细胞亚型的能力，因此可能在控制病毒感染中发挥重要作用。我们在一组慢性感染个体中研究了CD8(+) T(SCM)区室大小与HIV-1疾病进展之间的关系。我们的结果表明，HAART可恢复CD8(+) T(SCM)的正常频率，并且在未治疗的HIV-1感染情况下该亚群的自然保留与改善的病毒控制和免疫力相关。因此，CD8(+) T(SCM)群体可能代表慢性HIV-1感染中的一种保护相关因素，这与基于T细胞疫苗的设计、过继免疫治疗方法或T(SCM)的药理学诱导直接相关。
