Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China.
Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China.
Front Immunol. 2021 Dec 14;12:793375. doi: 10.3389/fimmu.2021.793375. eCollection 2021.
Mitochondrial DNA (mtDNA) profiles and contributions of mtDNA variants to CD4+T-cell recovery in Euramerican people living with HIV (PLWH) may not be transferred to East-Asian PLWH, highlighting the need to consider more regional studies. We aimed to identify mtDNA characteristics and mutations that explain the variability of short-term CD4+T-cell recovery in East-Asian PLWH.
Eight hundred fifty-six newly reported antiretroviral therapy (ART)-naïve Chinese PLWH from the Comparative HIV and Aging Research in Taizhou (CHART) cohort (Zhejiang Province, Eastern China) were enrolled. MtDNA was extracted from peripheral whole blood of those PLWH at HIV diagnosis, amplified, and sequenced using polymerase chain reaction and gene array. Characterization metrics such as mutational diversity and momentum were developed to delineate baseline mtDNA mutational patterns in ART-naïve PLWH. The associations between mtDNA genome-wide single nucleotide variants and CD4+T-cell recovery after short-term (within ~48 weeks) ART in 724 PLWH were examined using bootstrapping median regressions.
Of 856 participants, 74.18% and 25.82% were male and female, respectively. The median age was 37 years; 94.51% were of the major Han ethnicity, and 69.04% and 28.62% were of the heterosexual and homosexual transmission, respectively. We identified 2,352 types of mtDNA mutations and mtDNA regions , , , or with highest mutational diversity or volume. Female PLWH rather than male PLWH at the baseline showed remarkable age-related uptrends of momentum and mutational diversity as well as correlations between CD4+T <200 (cells/μl) and age-related uptrends of mutational diversity in many mtDNA regions. After adjustments of important sociodemographic and clinical variables, m.1005T>C, m.1824T>C, m.3394T>C, m.4491G>A, m.7828A>G, m.9814T>C, m.10586G>A, m.12338T>C, m.13708G>A, and m.14308T>C (at the Bonferroni-corrected significance) were negatively associated with short-term CD4+T-cell recovery whereas m.93A>G, m.15218A>G, and m.16399A>G were positively associated with short-term CD4+T-cell recovery.
Our baseline mtDNA characterization stresses the attention to East-Asian female PLWH at risk of CD4+T-cell loss-related aging and noncommunicable chronic diseases. Furthermore, mtDNA variants identified in regression analyses account for heterogeneity in short-term CD4+T-cell recovery of East-Asian PLWH. These results may help individualize the East-Asian immune recovery strategies under complicated HIV management caused by CD4+T-cell loss.
线粒体 DNA（mtDNA）谱和 mtDNA 变异体对欧美人感染艾滋病毒（HIV）后 CD4+T 细胞恢复的贡献可能无法转移到东亚 HIV 感染者身上，这突出表明需要考虑更多的区域性研究。我们旨在确定 mtDNA 特征和突变，以解释东亚 HIV 感染者短期 CD4+T 细胞恢复的可变性。
从中国浙江省台州艾滋病毒与衰老比较研究（CHART）队列（856 名）中纳入了 856 名新报告的抗逆转录病毒治疗（ART）初治的中国 HIV 感染者。在 HIV 诊断时，从这些 HIV 感染者的外周全血中提取 mtDNA，使用聚合酶链反应和基因芯片进行扩增和测序。开发了特征度量，如突变多样性和动力，以描绘 ART 初治 HIV 感染者基线 mtDNA 突变模式。在 724 名 HIV 感染者中，使用 bootstrap 中位数回归分析了 mtDNA 全基因组单核苷酸变异与短期（48 周内）ART 后 CD4+T 细胞恢复之间的关联。
在 856 名参与者中，分别有 74.18%和 25.82%为男性和女性。中位年龄为 37 岁；94.51%为汉族，分别有 69.04%和 28.62%为异性恋和同性恋传播。我们鉴定出 2352 种 mtDNA 突变和 mtDNA 区域、、、或，它们具有最高的突变多样性或体积。基线时女性 HIV 感染者而非男性 HIV 感染者的动力和突变多样性表现出明显的年龄相关上升趋势，并且 CD4+T<200（细胞/μl）与许多 mtDNA 区域的年龄相关上升趋势之间存在相关性。在调整了重要的社会人口统计学和临床变量后，m.1005T>C、m.1824T>C、m.3394T>C、m.4491G>A、m.7828A>G、m.9814T>C、m.10586G>A、m.12338T>C、m.13708G>A 和 m.14308T>C（在 Bonferroni 校正的显著性水平）与短期 CD4+T 细胞恢复呈负相关，而 m.93A>G、m.15218A>G 和 m.16399A>G 与短期 CD4+T 细胞恢复呈正相关。
我们的基线 mtDNA 特征强调了对处于 CD4+T 细胞丢失相关衰老和非传染性慢性疾病风险中的东亚女性 HIV 感染者的关注。此外，回归分析中鉴定的 mtDNA 变异体解释了东亚 HIV 感染者短期 CD4+T 细胞恢复的异质性。这些结果可能有助于在由 CD4+T 细胞丢失引起的复杂 HIV 管理下制定个体化的东亚免疫恢复策略。
