The HIV-1 reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time
The HIV-1 reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time
复制标题
DOI：
10.1073/pnas.1308313110
复制
发表时间：
2013-12-17
影响因子：
11.1
通讯作者：
Palmer, Sarah
中科院分区：
文献类型：
--
作者：
Josefsson, Lina;von Stockenstrom, Susanne;Palmer, Sarah
长期联合抗逆转录病毒治疗 (cART) 期间持续存在的 HIV-1 的来源和动态对于了解治愈 HIV-1 感染的障碍至关重要。为了解决这个问题，我们从 8 名经过 4-12 年抑制性 cART 治疗的患者的外周血和肠道相关淋巴组织 (GALT) 中的初始 T 细胞和记忆 T 细胞中分离出 HIV-1 DNA 并进行了基因表征。我们对这八名患者的详细分析表明，外周血和 GALT 中持续存在的 HIV-1 主要存在于记忆 CD4(+) T 细胞 [CD45RO(+)/CD27((+/-))] 中。与急性/早期感染相比，慢性感染期间开始治疗的患者外周血和 GALT 中 CD4(+) T 细胞的 HIV-1 感染频率较高，表明早期开始治疗会导致血液和肠道中 HIV-1 储存库的大小降低。系统发育分析显示，在 8 名患者中的 4 名患者中，在开始 cART 之前分离的 RNA 序列与抑制性 cART 4-12 年后 T 细胞亚群的细胞内 HIV-1 序列之间存在 HIV-1 遗传变化。然而，进化率分析估计在 4-12 年的抑制治疗期间，每个基因区域分析的核苷酸取代不超过 3 个。我们还在一名患者的多个记忆 T 细胞中发现了一个明显无法复制的病毒序列，强烈支持含有整合的 HIV-1 DNA 作为来源的细胞的异步细胞复制。这项研究表明，受感染记忆细胞群体的持续存在非常稳定，将是治愈的主要障碍，并且，在几乎没有病毒复制的证据的情况下，该群体可以通过稳态细胞增殖或其他过程来维持。
The source and dynamics of persistent HIV-1 during long-term combinational antiretroviral therapy (cART) are critical to understanding the barriers to curing HIV-1 infection. To address this issue, we isolated and genetically characterized HIV-1 DNA from naive and memory T cells from peripheral blood and gut-associated lymphoid tissue (GALT) from eight patients after 4-12 y of suppressive cART. Our detailed analysis of these eight patients indicates that persistent HIV-1 in peripheral blood and GALT is found primarily in memory CD4(+) T cells [CD45RO(+)/CD27((+/-))]. The HIV-1 infection frequency of CD4(+) T cells from peripheral blood and GALT was higher in patients who initiated treatment during chronic compared with acute/early infection, indicating that early initiation of therapy results in lower HIV-1 reservoir size in blood and gut. Phylogenetic analysis revealed an HIV-1 genetic change between RNA sequences isolated before initiation of cART and intracellular HIV-1 sequences from the T-cell subsets after 4-12 y of suppressive cART in four of the eight patients. However, evolutionary rate analyses estimated no greater than three nucleotide substitutions per gene region analyzed during all of the 4-12 y of suppressive therapy. We also identified a clearly replication incompetent viral sequence in multiple memory T cells in one patient, strongly supporting asynchronous cell replication of a cell containing integrated HIV-1 DNA as the source. This study indicates that persistence of a remarkably stable population of infected memory cells will be the primary barrier to a cure, and, with little evidence of viral replication, this population could be maintained by homeostatic cell proliferation or other processes.