Within-host dynamics of the hepatitis C virus quasispecies population in HIV-1/HCV coinfected patients.
Within-host dynamics of the hepatitis C virus quasispecies population in HIV-1/HCV coinfected patients.
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DOI：
10.1371/journal.pone.0016551
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发表时间：
2011-01-31
期刊：
影响因子：
3.7
通讯作者：
Zehender G
中科院分区：
文献类型：
--
作者：
Bernini F;Ebranati E;De Maddalena C;Shkjezi R;Milazzo L;Lo Presti A;Ciccozzi M;Galli M;Zehender G
接受高效抗逆转录病毒治疗(HAART)的HIV/丙型肝炎病毒混合感染者代表了一个有趣的模型，用于研究免疫系统在推动丙型肝炎病毒准种进化中所起的作用。我们前瞻性地研究了8名合并感染的患者的宿主内丙型肝炎病毒异质性的演变，这些患者是从32名启动HAART的患者中挑选出来的：5名免疫应答者(A组)和3名免疫无应答者(B组)，以及2名未服用药物的丙型肝炎病毒单独感染对照组(C组)。对于所有这些受试者，至少有两个在第一次观察(在HAART之前)和一年多后获得的序列样本进行了部分E1/E2序列的克隆序列分析，包括整个HVR1。用贝叶斯马尔可夫链蒙特卡罗方法联合估计进化速率、过时的系统发育和种群动态，并用基于最大似然法的方法估计特定地点的选择压力。丙型肝炎病毒准种在接受抗逆转录病毒治疗的受试者体内的进化速度是非免疫缺陷对照组的10倍(A组和B组分别为1.90和2.3万−3亚基/位/月，C组为0.29×10−3亚基/位/月)。宿主内的贝叶斯天际图分析显示，免疫应答者中的准种种群呈指数增长，与CD4细胞计数的峰值一致。与之相反，B组和C组的准种种群数量保持不变。在接受HAART的患者中，有一半的患者检测到显著的正选择压力，而在C组对照组中没有检测到。描述了几个在显著正选择下的位置，主要包括在HVR1中。我们的数据表明，在HAART免疫恢复期间，除了选择压力之外，不同的力量还推动了丙型肝炎病毒异常快速的演变。我们假设病毒复制空间的扩大起到了重要作用。
HIV/HCV coinfected individuals under highly active antiretroviral therapy (HAART) represent an interesting model for the investigation of the role played by the immune system in driving the evolution of the HCV quasispecies. We prospectively studied the intra-host evolution of the HCV heterogeneity in 8 coinfected subjects, selected from a cohort of 32 patients initiating HAART: 5 immunological responders (group A) and 3 immunological non-responders (group B), and in two HCV singly infected controls not assuming drugs (group C). For all these subjects at least two serial samples obtained at the first observation (before HAART) and more than 1 year later, underwent clonal sequence analysis of partial E1/E2 sequences, encompassing the whole HVR1. Evolutionary rates, dated phylogenies and population dynamics were co-estimated by using a Bayesian Markov Chain Monte Carlo approach, and site specific selection pressures were estimated by maximum likelihood-based methods. The intra-host evolutionary rates of HCV quasispecies was 10 times higher in subjects treated with HAART than in controls without immunodeficiency (1.9 and 2.3×10−3 sub/site/month in group A and B and 0.29×10−3 sub/site/month in group C individuals). The within-host Bayesian Skyline plot analysis showed an exponential growth of the quasispecies populations in immunological responders, coinciding with a peak in CD4 cell counts. On the contrary, quasispecies population remained constant in group B and in group C controls. A significant positive selection pressure was detected in a half of the patients under HAART and in none of the group C controls. Several sites under significant positive selection were described, mainly included in the HVR1. Our data indicate that different forces, in addition to the selection pressure, drive an exceptionally fast evolution of HCV during HAART immune restoration. We hypothesize that an important role is played by the enlargement of the viral replicative space.
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