Liu Pengtao, Feng Yi, Wu Jianjun, Tian Suian, Su Bin, Wang Zhe, Liao Lingjie, Xing Hui, You Yinghui, Shao Yiming, Ruan Yuhua
State Key Laboratory of Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing, China.
Anhui Center for Disease Control and Prevention, Hefei, Anhui Province, China.
PLoS One. 2017 Jan 18;12(1):e0170139. doi: 10.1371/journal.pone.0170139. eCollection 2017.
HIV drug resistance is associated with faster clinical progression of AIDS. However, the effect of significant polymorphisms and mutational covariation on mortality among HIV/AIDS patients receiving long-term antiretroviral therapy (ART), have rarely been studied.
In this prospective cohort study from December 2003 to December 2014, we present a new computational modelling approach based on bioinformatics-based models and several statistical methods to elucidate the molecular mechanisms involved in the acquisition of polymorphisms and mutations on death in HIV/AIDS patients receiving long-term ART in China.
This study involved 654 ART-treated patients, who had been followed for 5473.4 person-years, a median of 9.8 years, and 178 died (25.2%, 3.3/100 person-years). The first regimens included AZT/d4T + NVP+ ddI (78.9%) or AZT/d4T + NVP+ 3TC (20.0%). We calculated an individual Ka/Ks value for each specific amino acid mutation. Result showed that 20 polymorphisms (E6D, Q18H, E35D, S37N, T39A, K43E, S68N, L74I, I93L, K103N, V106A, E169D, Y181C, G190A, Q197K, T200V, T200E, T215I, E224D and P225H) were strongly associated with AIDS related deaths. Among them, 7 polymorphisms (L74I, K103N, V106A, Y181C, G190A, T215I and P225H) were known to be drug resistance mutations, 7 polymorphisms (E6D, E35D, S37N, I93L, E169D, T200V and T200E were considered to be potential drug resistance mutations, and 6 polymorphisms (T39A, K43E, S68N, Q197K, T200V and E224D) were newly found to have an association with drug resistance mutations, which formed a complex network of relationships.
Some polymorphisms and mutational covariation may be the important influencing factors in the failure of treatment. Understanding these mechanisms is essential for the development of new therapies, designing optimal drug combinations, and determining effective clinical management of individual patients.
HIV耐药性与艾滋病临床进展加快相关。然而，对于接受长期抗逆转录病毒治疗（ART）的HIV/AIDS患者，显著的多态性和突变共变对死亡率的影响鲜有研究。
在这项从2003年12月至2014年12月的前瞻性队列研究中，我们提出了一种基于生物信息学模型和多种统计方法的新计算建模方法，以阐明中国接受长期ART的HIV/AIDS患者中多态性和突变与死亡相关的分子机制。
本研究纳入654例接受ART治疗的患者，随访5473.4人年，中位数为9.8年，178例死亡（25.2%，3.3/100人年）。初始治疗方案包括AZT/d4T + NVP + ddI（78.9%）或AZT/d4T + NVP + 3TC（20.0%）。我们计算了每个特定氨基酸突变的个体Ka/Ks值。结果显示，20种多态性（E6D、Q18H、E35D、S37N、T39A、K43E、S68N、L74I、I93L、K103N、V106A、E169D、Y181C、G190A、Q197K、T200V、T200E、T215I、E224D和P225H）与艾滋病相关死亡密切相关。其中，7种多态性（L74I、K103N、V106A、Y181C、G190A、T215I和P225H）已知为耐药突变，7种多态性（E6D、E35D、S37N、I93L、E169D、T200V和T200E）被认为是潜在耐药突变，6种多态性（T39A、K43E、S68N、Q197K、T200V和E224D）新发现与耐药突变有关，它们形成了一个复杂的关系网络。
一些多态性和突变共变可能是治疗失败的重要影响因素。了解这些机制对于开发新疗法、设计最佳药物组合以及确定个体患者的有效临床管理至关重要。
