Drug Resistance Mutation Frequency of Single-Genome Amplification-Derived HIV-1 Polymerase Genomes in the Cerebrospinal Fluid and Plasma of HIV-1-Infected Individuals under Nonsuppressive Therapy.
Drug Resistance Mutation Frequency of Single-Genome Amplification-Derived HIV-1 Polymerase Genomes in the Cerebrospinal Fluid and Plasma of HIV-1-Infected Individuals under Nonsuppressive Therapy.
复制标题
非抑制治疗下 HIV-1 感染者脑脊液和血浆中单基因组扩增衍生的 HIV-1 聚合酶基因组的耐药突变频率。
DOI：
10.1128/jvi.01824-19
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发表时间：
2020
影响因子：
5.4
通讯作者：
Evering,TeresaH
中科院分区：
文献类型：
--
作者：
StBernard,Leslie;Abolade,Jeremy;Mohri,Hiroshi;Markowitz,Martin;Evering,TeresaH
HIV-1 在脑脊液 (CSF) 和血浆中的进化可能会导致区室中不一致的耐药突变 (DRM)。使用单基因组扩增 (SGA) 在 CNS HIV 抗逆转录病毒治疗效果研究 (CHARTER) 研究中的 12 名 HIV-1 阳性参与者的配对脑脊液和血浆样本中生成部分 HIV-1 聚合酶基因组，这些参与者被分类为神经认知未受损或患有不同程度的 HIV 相关神经认知障碍 (HAND)。接受联合抗逆转录病毒治疗（cART）的受试者出现病毒血症。 HIV-1 DRM 和系统发育特征是使用斯坦福 HIVdb 程序和系统发育分析确定的。与成对的脑脊液相比，个体 DRM 在血浆中的识别率更高 (P =0.0078)。在 3 名 HAND 患者中发现 CSF 和血浆中 DRM 的比例存在显着差异 (3/7 = 43%)。两名 HAND 受试者（2/7 = 29%）在脑脊液中表现出一种在配对血浆中未发现的 DRM。纵向分析 (n= 4) 显示各隔室中 DRM 比率存在显着的时间差异。在接受非抑制性 cART 治疗的患者中，很容易发现脑脊液和血浆中 DRM 频率存在统计学上的显着差异。虽然基于区室的 DRM 不一致在很大程度上与血浆中药物选择性压力的增加一致，但中枢神经系统 (CNS) 中可能会出现 DRM 的过度表达。 HAND 的潜在机制是复杂且多因素的。 DRM 不一致对病毒持久性和 HAND 发病机制的临床影响仍不清楚，需要在更大的纵向队列中进行进一步研究。 重要性 几种抗逆转录病毒药物不能有效进入中枢神经系统，中枢神经系统和血浆中可能会发生 HIV-1 病毒变异体的独立进化。我们在横断面和纵向分析中使用单基因组扩增（SGA）来独特地定义病毒抑制不完全且神经认知状态已知的个体的脑脊液（CSF）和血浆中个体HIV-1聚合酶基因组的耐药突变（DRM）的身份和相对比例。在接受非抑制性 cART 的患者中，很容易发现脑脊液和血浆中 DRM 的比例存在统计学上的显着差异，并且中枢神经系统中的 DRM 可能会出现过高的情况。尽管关于 DRM 不一致的临床意义的问题仍然存在，但在寻求病毒根除的过程中，重要的是要认识到可能存在显着的、动态的、基于区室的 DRM 比例失衡，因为它有可能在标准临床耐药性测试的设置中被忽视。
HIV-1 evolution in the cerebrospinal fluid (CSF) and plasma may result in discordant drug resistance mutations (DRMs) in the compartments. Single-genome amplification (SGA) was used to generate partial HIV-1 polymerase genomes in paired CSF and plasma samples from 12 HIV-1-positive participants in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study who were classified as neurocognitively unimpaired or with various degrees of HIV-associated neurocognitive disorders (HAND). Subjects were viremic on combination antiretroviral therapy (cART). HIV-1 DRMs and phylogenetic characteristics were determined using the Stanford HIVdb program and phylogenetic analyses. Individual DRMs were identified more frequently in plasma than in paired CSF (P =0.0078). Significant differences in the ratios of DRMs in CSF and plasma were found in 3 individuals with HAND (3/7 = 43%). Two HAND subjects (2/7 = 29%) demonstrated one DRM in CSF not identified in paired plasma. Longitudinal analyses (n= 4) revealed significant temporal differences in the ratios of DRMs in the compartments. Statistically significant differences in the frequency of DRMs in the CSF and plasma are readily found in those on nonsuppressive cART. While compartment-based DRM discordance was largely consistent with increased drug-selective pressures in the plasma, overrepresentation of DRMs in the central nervous system (CNS) can occur. Underlying mechanisms of HAND are complex and multifactorial. The clinical impact of DRM discordance on viral persistence and HAND pathogenesis remains unclear and warrants further investigation in larger, longitudinal cohorts.IMPORTANCESeveral antiretroviral agents do not efficiently enter the CNS, and independent evolution of HIV-1 viral variants in the CNS and plasma can occur. We used single-genome amplification (SGA) in cross-sectional and longitudinal analyses to uniquely define both the identity and relative proportions of drug resistance mutations (DRMs) on individual HIV-1 polymerase genomes in the cerebrospinal fluid (CSF) and plasma in individuals with incomplete viral suppression and known neurocognitive status. Statistically significant differences in the ratio of DRMs in the CSF and plasma were readily found in those on nonsuppressive cART, and overrepresentation of DRMs in the CNS can occur. Although questions about the clinical significance of DRM discordance remain, in the quest for viral eradication, it is important to recognize that a significant, dynamic, compartment-based DRM ratio imbalance can exist, as it has the potential to go unnoticed in the setting of standard clinical drug resistance testing.