Abstract
BackgroundWhether 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.Methods and FindingsIn 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.ConclusionsThe 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.
Highlights
The last few years have witnessed an unprecedented interest and effort in identifying the genetic determinants that underlie susceptibility to human diseases
By tracking a unique aspect of AIDS risk distinct from that captured by the laboratory parameters, CCL3L1CCR5 genotypes may have utility in HIV clinical management
A possible role for these genetic markers in evaluation of AIDS risk was underscored by the observation that CC chemokine ligand 3-like 1 (CCL3L1)-chemokine receptor 5 (CCR5) genetic risk group (GRG) status predicted HIV disease course independent of the viral load and CD4+ T cell count as well as other explanatory variables that were in themselves independent markers of disease progression [20]. The latter associations were observed in two separate and large groups of subjects who within the context of a natural HIV-1 history cohort were followed prospectively from the early stages of their infection [20]. These findings suggested that there is a component of AIDS risk that is genetically-defined by CCL3L1-CCR5 genetic variations which may not be captured fully by the laboratory markers
Summary
The last few years have witnessed an unprecedented interest and effort in identifying the genetic determinants that underlie susceptibility to human diseases. A framework of how to assess fully whether such genetic information might help improve the clinical management of patients remains unclear, especially when compared to laboratory markers that are considered the gold standard in evaluating disease prognosis To address this gap in knowledge we used (i) HIV infection, (ii) variations in the genes encoding CC chemokine receptor 5 (CCR5), the major coreceptor for HIV-1 [1], and CC chemokine ligand 3-like 1 (CCL3L1), the most potent CCR5 agonist and HIV-suppressive chemokine [2,3,4,5], and (iii) the laboratory markers (CD4+ T cell count and viral load) currently used to evaluate HIV-infected patients, as a model system. We determined whether accounting for both genetic and laboratory markers provided an improved means of assessing AIDS risk
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