Kulkarni Hemant, Agan Brian K, Marconi Vincent C, O'Connell Robert J, Camargo Jose F, He Weijing, Delmar Judith, Phelps Kenneth R, Crawford George, Clark Robert A, Dolan Matthew J, Ahuja Sunil K
Veterans Administration Research Center for AIDS and HIV-1 Infection, South Texas Veterans Health Care System, San Antonio, Texas, United States of America.
PLoS One. 2008 Sep 8;3(9):e3165. doi: 10.1371/journal.pone.0003165.
Whether vexing clinical decision-making dilemmas can be partly addressed by recent advances in genomics is unclear. For example, when to initiate highly active antiretroviral therapy (HAART) during HIV-1 infection remains a clinical dilemma. This decision relies heavily on assessing AIDS risk based on the CD4+ T cell count and plasma viral load. However, the trajectories of these two laboratory markers are influenced, in part, by polymorphisms in CCR5, the major HIV coreceptor, and the gene copy number of CCL3L1, a potent CCR5 ligand and HIV-suppressive chemokine. Therefore, we determined whether accounting for both genetic and laboratory markers provided an improved means of assessing AIDS risk.
In a prospective, single-site, ethnically-mixed cohort of 1,132 HIV-positive subjects, we determined the AIDS risk conveyed by the laboratory and genetic markers separately and in combination. Subjects were assigned to a low, moderate or high genetic risk group (GRG) based on variations in CCL3L1 and CCR5. The predictive value of the CCL3L1-CCR5 GRGs, as estimated by likelihood ratios, was equivalent to that of the laboratory markers. GRG status also predicted AIDS development when the laboratory markers conveyed a contrary risk. Additionally, in two separate and large groups of HIV+ subjects from a natural history cohort, the results from additive risk-scoring systems and classification and regression tree (CART) analysis revealed that the laboratory and CCL3L1-CCR5 genetic markers together provided more prognostic information than either marker alone. Furthermore, GRGs independently predicted the time interval from seroconversion to CD4+ cell count thresholds used to guide HAART initiation.
The combination of the laboratory and genetic markers captures a broader spectrum of AIDS risk than either marker alone. By tracking a unique aspect of AIDS risk distinct from that captured by the laboratory parameters, CCL3L1-CCR5 genotypes may have utility in HIV clinical management. These findings illustrate how genomic information might be applied to achieve practical benefits of personalized medicine.
目前尚不清楚基因组学的最新进展能否部分解决令人困扰的临床决策困境。例如，在HIV-1感染期间何时开始高效抗逆转录病毒治疗（HAART）仍然是一个临床难题。这一决策很大程度上依赖于根据CD4 + T细胞计数和血浆病毒载量评估艾滋病风险。然而，这两个实验室指标的变化轨迹部分受主要HIV共受体CCR5的多态性以及强效CCR5配体和HIV抑制趋化因子CCL3L1的基因拷贝数影响。因此，我们确定综合考虑遗传和实验室指标是否能提供更好的评估艾滋病风险的方法。
在一个有1132名HIV阳性受试者的前瞻性、单中心、种族混合队列中，我们分别及综合确定了实验室指标和遗传指标所传达的艾滋病风险。根据CCL3L1和CCR5的变异情况，将受试者分为低、中、高遗传风险组（GRG）。通过似然比估计，CCL3L1 - CCR5 GRG的预测价值与实验室指标相当。当实验室指标传达相反风险时，GRG状态也能预测艾滋病的发展。此外，在来自自然史队列的两组独立且规模较大的HIV + 受试者中，相加风险评分系统和分类回归树（CART）分析结果显示，实验室指标和CCL3L1 - CCR5遗传指标共同提供的预后信息比单独任何一个指标都多。此外，GRG独立预测了从血清转化到用于指导开始HAART的CD4 + 细胞计数阈值的时间间隔。
与单独任何一个指标相比，实验室指标和遗传指标相结合能涵盖更广泛的艾滋病风险谱。通过追踪与实验室参数所捕捉的不同的艾滋病风险独特方面，CCL3L1 - CCR5基因型可能在HIV临床管理中具有实用价值。这些发现说明了基因组信息如何应用于实现个性化医疗的实际益处。
