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Longitudinal analysis of subtype C envelope tropism for memory CD4+ T cell subsets over the first 3 years of untreated HIV-1 infection
Retrovirology ( IF 3.3 ) Pub Date : 2020-08-06 , DOI: 10.1186/s12977-020-00532-2
Matthew J Gartner 1, 2 , Paul R Gorry 1 , Carolin Tumpach 2 , Jingling Zhou 1 , Ashanti Dantanarayana 2 , J Judy Chang 2 , Thomas A Angelovich 1, 3 , Paula Ellenberg 2 , Annemarie E Laumaea 1, 4 , Molati Nonyane 5 , Penny L Moore 5, 6, 7 , Sharon R Lewin 2, 8 , Melissa J Churchill 1 , Jacqueline K Flynn 1, 2, 9 , Michael Roche 1, 2
Affiliation  

HIV-1 infects a wide range of CD4+ T cells with different phenotypic properties and differing expression levels of entry coreceptors. We sought to determine the viral tropism of subtype C (C-HIV) Envelope (Env) clones for different CD4+ T cell subsets and whether tropism changes during acute to chronic disease progression. HIV-1 envs were amplified from the plasma of five C-HIV infected women from three untreated time points; less than 2 months, 1-year and 3-years post-infection. Pseudoviruses were generated from Env clones, phenotyped for coreceptor usage and CD4+ T cell subset tropism was measured by flow cytometry. A total of 50 C-HIV envs were cloned and screened for functionality in pseudovirus infection assays. Phylogenetic and variable region characteristic analysis demonstrated evolution in envs between time points. We found 45 pseudoviruses were functional and all used CCR5 to mediate entry into NP2/CD4/CCR5 cells. In vitro infection assays showed transitional memory (TM) and effector memory (EM) CD4+ T cells were more frequently infected (median: 46% and 25% of total infected CD4+ T cells respectively) than naïve, stem cell memory, central memory and terminally differentiated cells. This was not due to these subsets contributing a higher proportion of the CD4+ T cell pool, rather these subsets were more susceptible to infection (median: 5.38% EM and 2.15% TM cells infected), consistent with heightened CCR5 expression on EM and TM cells. No inter- or intra-participant changes in CD4+ T cell subset tropism were observed across the three-time points. CD4+ T cell subsets that express more CCR5 were more susceptible to infection with C-HIV Envs, suggesting that these may be the major cellular targets during the first 3 years of infection. Moreover, we found that viral tropism for different CD4+ T cell subsets in vitro did not change between Envs cloned from acute to chronic disease stages. Finally, central memory, naïve and stem cell memory CD4+ T cell subsets were susceptible to infection, albeit inefficiently by Envs from all time-points, suggesting that direct infection of these cells may help establish the latent reservoir early in infection.

中文翻译:

在未经治疗的 HIV-1 感染的前 3 年中,对记忆 CD4+ T 细胞亚群的 C 亚型包膜趋向性的纵向分析

HIV-1 感染多种具有不同表型特性和不同表达水平的进入辅助受体的 CD4+ T 细胞。我们试图确定不同 CD4+ T 细胞亚群的 C 亚型 (C-HIV) 包膜 (Env) 克隆的病毒趋向性,以及在急性到慢性疾病进展过程中趋向性是否发生变化。HIV-1 envs 从三个未治疗时间点的五名 C-HIV 感染女性的血浆中扩增出来;感染后不到 2 个月、1 年和 3 年。从 Env 克隆产生假病毒,对辅助受体的使用进行表型分析,并通过流式细胞术测量 CD4+T 细胞亚群的趋向性。总共克隆了 50 个 C-HIV envs 并筛选了假病毒感染测定中的功能。系统发育和可变区特征分析证明了时间点之间环境的进化。我们发现 45 种假病毒是有功能的,并且都使用 CCR5 介导进入 NP2/CD4/CCR5 细胞。体外感染试验表明,过渡性记忆 (TM) 和效应记忆 (EM) CD4+ T 细胞比幼稚、干细胞记忆、中央记忆和终末期感染更频繁(中位数:分别占总感染 CD4+ T 细胞的 46% 和 25%)分化的细胞。这不是因为这些亚群贡献了更高比例的 CD4+ T 细胞库,而是这些亚群更容易受到感染(中位数:5.38% EM 和 2.15% TM 细胞感染),与 EM 和 TM 细胞上的 CCR5 表达升高一致. 在三个时间点未观察到参与者间或参与者内 CD4+ T 细胞亚群趋向性的变化。表达更多 CCR5 的 CD4+ T 细胞亚群更容易感染 C-HIV Envs,这表明这些可能是感染前 3 年的主要细胞目标。此外,我们发现体外不同 CD4+ T 细胞亚群的病毒嗜性在从急性到慢性疾病阶段克隆的 Envs 之间没有变化。最后,中央记忆、幼稚和干细胞记忆 CD4+ T 细胞亚群易受感染,尽管在所有时间点都被 Envs 低效,这表明这些细胞的直接感染可能有助于在感染早期建立潜伏储存库。
更新日期:2020-08-06
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