Absence of HIV-1 evolution in the gut-associated lymphoid tissue from patients on combination antiviral therapy initiated during primary infection.
Absence of HIV-1 evolution in the gut-associated lymphoid tissue from patients on combination antiviral therapy initiated during primary infection.
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DOI：
10.1371/journal.ppat.1002506
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发表时间：
2012-02
期刊：
影响因子：
6.7
通讯作者：
Markowitz M
中科院分区：
文献类型：
--
作者：
Evering TH;Mehandru S;Racz P;Tenner-Racz K;Poles MA;Figueroa A;Mohri H;Markowitz M
胃肠道 (GI) 的粘膜单核 (MMC) CCR5+CD4+ T 细胞在急性 HIV-1 感染期间被选择性感染和耗尽。尽管早期开始联合抗逆转录病毒治疗 (cART)，但在大多数研究的 HIV-1 阳性个体中，肠道相关淋巴组织 (GALT) CD4+ T 细胞的消耗和激活仍然持续存在。尽管 cART 有效，但这可能是由于 HIV-1 复制和 T 细胞持续激活所致。我们假设 cART 期间胃肠道中持续的病毒复制将导致可测量的病毒进化，随着时间的推移会出现不同的种群。在早期 HIV-1 感染期间接受治疗的受试者在 cART 开始之前和之后 15-24 个月接受了静脉切开术和柔性乙状结肠镜活检以及活检。在第二次活检时，发现三种 GALT 表型，其特征是高、中和低水平的免疫激活。分析了每种表型的代表性病例。每个受试者在第二次胃肠道活检和外周血中 CD4+ T 细胞重建时血浆 HIV-1 RNA 水平<50 拷贝/ml。在 GALT 和 PBMC 中开始 cART 之前和之后，对每个受试者进行全长 HIV-1 包膜的单基因组扩增。总共对280个已确认的单基因组序列（SGS）进行了实验案例分析。对于每个受试者，从分子序列数据得出的最大似然系统发育树显示，在研究期间没有 GALT 进化形式的证据。在治疗期间，GALT 衍生的 SGS 中的 HIV-1 包膜多样性没有增加，治疗后 GALT 衍生的 SGS 显示与传播组内的治疗前序列没有显着的遗传差异。从 PBMC 衍生的 SGS 中获得了类似的结果。我们的结果表明，在急性/早期 HIV-1 感染期间启动 cART 可能会导致 GALT 中可测量的病毒进化中断，这表明在抑制性 cART 期间，该区室中不存在 HIV-1 的从头复制。这项研究的目的是确定胃肠道是否是抑制性联合抗逆转录病毒治疗 (cART) 期间病毒持续复制的部位（定义为血浆 HIV-1 RNA 水平低于 50 拷贝/毫升）。我们没有发现证据表明，在早期 HIV-1 感染期间开始 cART 的参与者中，源自外周血单核细胞或胃肠道淋巴组织细胞的 HIV-1 包膜序列发生了实质性病毒进化。据我们所知，这是单基因组扩增技术首次应用于来自胃肠道的 HIV-1 准物种的比较分析，表明在这些个体中，cART 能够阻止该区室中 HIV-1 包膜的可测量进化。这些发现表明，在抑制性 cART 期间不存在 HIV-1 的从头复制，并且通过实验观察到，在早期开始和不间断使用 cART 后观察到的胃肠道淋巴组织中免疫激活水平持续升高（尽管血液中的相对免疫重建）可能是由于病毒复制以外的因素造成的。这意味着，在病毒受到抑制的人群中，cART 强化不太可能显着影响持续的 CD4+ T 细胞耗竭或胃肠道中免疫激活水平的增加。
Mucosal mononuclear (MMC) CCR5+CD4+ T cells of the gastrointestinal (GI) tract are selectively infected and depleted during acute HIV-1 infection. Despite early initiation of combination antiretroviral therapy (cART), gut-associated lymphoid tissue (GALT) CD4+ T cell depletion and activation persist in the majority of HIV-1 positive individuals studied. This may result from ongoing HIV-1 replication and T-cell activation despite effective cART. We hypothesized that ongoing viral replication in the GI tract during cART would result in measurable viral evolution, with divergent populations emerging over time. Subjects treated during early HIV-1 infection underwent phlebotomy and flexible sigmoidoscopy with biopsies prior to and 15–24 months post initiation of cART. At the 2nd biopsy, three GALT phenotypes were noted, characterized by high, intermediate and low levels of immune activation. A representative case from each phenotype was analyzed. Each subject had plasma HIV-1 RNA levels <50 copies/ml at 2nd GI biopsy and CD4+ T cell reconstitution in the peripheral blood. Single genome amplification of full-length HIV-1 envelope was performed for each subject pre- and post-initiation of cART in GALT and PBMC. A total of 280 confirmed single genome sequences (SGS) were analyzed for experimental cases. For each subject, maximum likelihood phylogenetic trees derived from molecular sequence data showed no evidence of evolved forms in the GALT over the study period. During treatment, HIV-1 envelope diversity in GALT-derived SGS did not increase and post-treatment GALT-derived SGS showed no substantial genetic divergence from pre-treatment sequences within transmitted groups. Similar results were obtained from PBMC-derived SGS. Our results reveal that initiation of cART during acute/early HIV-1 infection can result in the interruption of measurable viral evolution in the GALT, suggesting the absence of de-novo rounds of HIV-1 replication in this compartment during suppressive cART. This study was undertaken to determine if the gastrointestinal tract is a site of ongoing viral replication during suppressive combination antiretroviral therapy (cART) (defined by plasma HIV-1 RNA levels below 50 copies/ml). We found no evidence of substantial viral evolution in HIV-1 envelope sequences derived from peripheral blood mononuclear cells or cells of the gastrointestinal tract lymphoid tissue in participants initiating cART during early HIV-1 infection. To our knowledge, this is the first application of the single genome amplification technique to the comparative analysis of HIV-1 quasi-species derived from the gastrointestinal tract, demonstrating that in these individuals, cART has the ability to halt measurable evolution of HIV-1 envelope in this compartment. These findings suggest the absence of de-novo rounds of HIV-1 replication during suppressive cART and by extension, that experimentally observed, persistently elevated levels of immune activation in the gastrointestinal lymphoid tissue seen after the early initiation and uninterrupted use of cART (despite relative immune reconstitution in the blood) is likely due to factors other than ongoing viral replication. This implies that in this virally suppressed population, cART intensification is unlikely to significantly impact persistent CD4+ T cell depletion or increased levels of immune activation in the gastrointestinal tract.
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DOI：
10.1073/pnas.95.15.8869
发表时间：
1998-07-21
影响因子：
11.1
作者：
Chun, TW;Engel, D;Fauci, AS
通讯作者：
Fauci, AS
影响因子：
1.5
作者：
Benito, JM;López, M;Soriano, V
通讯作者：
Soriano, V
雌性生殖道内HIV-1的隔室化是由于单型和低多样性变体而不是不同的病毒群体引起的。
影响因子：
3.7
作者：
Bull M;Learn G;Genowati I;McKernan J;Hitti J;Lockhart D;Tapia K;Holte S;Dragavon J;Coombs R;Mullins J;Frenkel L
通讯作者：
Frenkel L
使用细胞因子的组合在潜在感染的CD4+ T细胞中诱导HIV-1复制。
DOI：
10.1084/jem.188.1.83
发表时间：
1998-07-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
通讯作者：
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影响因子：
3.8
作者：
Anton, PA;Elliott, J;Giorgi, JV
通讯作者：
Giorgi, JV