Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells
Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells
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DOI：
10.1038/nature03513
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发表时间：
2005-04-28
期刊：
影响因子：
64.8
通讯作者：
Haase, AT
中科院分区：
文献类型：
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作者：
Li, QS;Duan, LJ;Haase, AT
在早期猿猴免疫缺陷病毒 (SIV) 和人类免疫缺陷病毒 1 (HIV-1) 感染中，肠道相关淋巴组织 (GALT) 作为淋巴器官系统的最大组成部分(1)，是病毒产生和主要固有层记忆 CD4(+) T 细胞耗竭的主要部位；也就是说，表达 CD4 的 T 细胞先前遇到抗原和微生物并归巢于 GALT(2-9) 固有层。在这里，我们发现感染 SIV 的恒河猴肠道组织中病毒产量的峰值与受感染的记忆 CD4(+) T 细胞的峰值数量一致。令人惊讶的是，大多数最初感染的记忆细胞并没有像预期的那样被激活 (10,11)，而是免疫表型“休眠”细胞，与真正的休眠细胞不同，它们与主要在其他粘膜部位和周围淋巴结感染的第一批细胞一样 (12,13)，能够支持病毒的产生。除了诱导免疫激活并从而提供激活的 CD4(+) T 细胞靶标来维持感染外，病毒产生还触发 (14) 固有层 CD4(+) T 细胞中免疫病理学上限制 Fas-Fas 配体介导的凋亡途径 (15,16)，从而导致其优先消融。因此，SIV利用GALT中大量常驻的静息记忆CD4+T细胞来产生峰值水平的病毒，直接（通过裂解感染）和间接（通过感染和未感染细胞的凋亡）消耗GALT效应臂中的CD4+T细胞。这种 CD4(+) T 细胞耗竭的规模对宿主的免疫系统产生不利影响，这强调了在 GALT 感染之前制定有效的 SIV 对策的重要性。
In early simian immunodeficiency virus (SIV) and human immunodeficiency virus-1 (HIV-1) infections, gut-associated lymphatic tissue (GALT), the largest component of the lymphoid organ system(1), is a principal site of both virus production and depletion of primarily lamina propria memory CD4(+) T cells; that is, CD4-expressing T cells that previously encountered antigens and microbes and homed to the lamina propria of GALT(2-9). Here, we show that peak virus production in gut tissues of SIV-infected rhesus macaques coincides with peak numbers of infected memory CD4(+) T cells. Surprisingly, most of the initially infected memory cells were not, as expected(10,11), activated but were instead immunophenotypically 'resting' cells that, unlike truly resting cells, but like the first cells mainly infected at other mucosal sites and peripheral lymph nodes(12,13), are capable of supporting virus production. In addition to inducing immune activation and thereby providing activated CD4(+) T-cell targets to sustain infection, virus production also triggered(14) an immunopathologically limiting Fas-Fas-ligand-mediated apoptotic pathway(15,16) in lamina propria CD4(+) T cells, resulting in their preferential ablation. Thus, SIV exploits a large, resident population of resting memory CD4(+) T cells in GALT to produce peak levels of virus that directly (through lytic infection) and indirectly ( through apoptosis of infected and uninfected cells) deplete CD4(+) T cells in the effector arm of GALT. The scale of this CD4(+) T-cell depletion has adverse effects on the immune system of the host, underscoring the importance of developing countermeasures to SIV that are effective before infection of GALT.