Ho Sarah K, Perez Elena E, Rose Stephanie L, Coman Roxana M, Lowe Amanda C, Hou Wei, Ma Changxing, Lawrence Robert M, Dunn Ben M, Sleasman John W, Goodenow Maureen M
Department of Pathology, Immunology, and Laboratory Medicine, University at Buffalo, University of Florida College of Medicine,Gainesville, USA.
AIDS. 2009 Aug 24;23(13):1631-40. doi: 10.1097/QAD.0b013e32832e0599.
To identify novel viral determinants in HIV-1 protease, Gag, and envelope V3 that relate to outcomes to initial protease inhibitor-based antiretroviral therapy.
A longitudinal cohort study of protease inhibitor-naive, HIV-infected individuals was designed to identify genetic variables in viral Gag and envelope sequences associated with response to antiretroviral therapy.
Genetic and statistical models, including amino acid profiles, phylogenetic analyses, receiver operating characteristic analyses, and covariation analyses, were used to evaluate viral sequences and clinical variables from individuals who developed immune reconstitution with or without suppression of viral replication.
Pretherapy chemokine (C-X-C motif) receptor 4-using V3 regions had significant associations with viral failure (P = 0.04). Amino acid residues in protease covaried with Gag residues, particularly in p7(NC), independent of cleavage sites. Pretherapy V3 charge combined with p6(Pol) and p2/p7(NC) cleavage site genotypes produced the best three-variable model to predict viral suppression in 88% of individuals. Combinations of baseline CD4 cell percentage with genetic determinants in Gag-protease predicted viral fitness in 100% of individuals who failed to suppress viral replication.
Baseline genetic determinants in Gag p6(Pol) and p2/p7(NC), as well as envelope, provide novel combinations of biomarkers for predicting emergence of viral resistance to initial therapy regimens.
确定人类免疫缺陷病毒1型（HIV-1）蛋白酶、群抗原（Gag）和包膜V3区中与基于蛋白酶抑制剂的初始抗逆转录病毒治疗结果相关的新型病毒决定因素。
一项针对未接受过蛋白酶抑制剂治疗的HIV感染者的纵向队列研究，旨在确定病毒Gag和包膜序列中与抗逆转录病毒治疗反应相关的基因变量。
使用包括氨基酸谱、系统发育分析、受试者工作特征分析和共变分析在内的遗传和统计模型，评估出现免疫重建且病毒复制得到或未得到抑制的个体的病毒序列和临床变量。
治疗前趋化因子（C-X-C基序）受体4使用的V3区与病毒治疗失败显著相关（P = 0.04）。蛋白酶中的氨基酸残基与Gag残基共变，特别是在p7（核衣壳蛋白，NC）中，与切割位点无关。治疗前V3电荷与p6（聚合酶，Pol）和p2/p7（NC）切割位点基因型相结合，产生了最佳的三变量模型，可预测88%个体的病毒抑制情况。基线CD4细胞百分比与Gag-蛋白酶中的遗传决定因素相结合，可预测100%病毒复制未得到抑制个体的病毒适应性。
Gag p6（Pol）和p2/p7（NC）以及包膜中的基线遗传决定因素，为预测对初始治疗方案的病毒耐药性出现提供了新的生物标志物组合。
