Hemant Kulkarni, Brian K. Agan, Vincent C. Marconi, Robert J. O'Connell, Jose F. Camargo, Weijing He, Judith Delmar, Kenneth R. Phelps, George Crawford, Robert A. Clark, Matthew J. Dolan, Sunil K. Ahuja

“ Discussion In this study, we tested the hypothesis that in conjunction with laboratory markers currently used to assess AIDS risk, the complex patterns of genetic variations in the human genome may have utility as tools for improved risk assessment of patients infected with HIV-1. ”

“ 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. ”

“ These findings also have value for improving our understanding of the factors that influence HIV-AIDS pathogenesis and for the interpretation of genotype-phenotype association studies in general. The ability of the GRGs to provide an additive measure of AIDS risk, including in those with high CD4 cell counts, suggests that the impact of these host factors during chronic infection is partly through viral load-independent mechanisms that are likely operative in the proximal end of the causal pathways that affect CD4 cell loss and establishment of the steady-state viral load. ”

“ Conclusions 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.
Introduction The last few years have witnessed an unprecedented interest and effort in identifying the genetic determinants that underlie susceptibility to human diseases. ”

“ The preceding findings underscored that over and above the AIDS risk conveyed by the CD4 cell count and viral load, CCL3L1-CCR5 GRG status may serve as a unique parameter to identify HIV-infected individuals who are at an increased risk of developing AIDS. To investigate further this possibility, we considered whether GRGs and laboratory markers can be combined in a clinically meaningful way to enhance AIDS prognostication. ”

“ The pretest probability of developing AIDS in the entire cohort and the seroconverting component of the cohort in whom CCL3L1-CCR5 genotype was determined was 39% and 27%, respectively. However, the post-test probabilities of developing AIDS differed according to a person's GRG or CD4 cell count (Table 1) . ”

“ In the first approach, we used a risk scoring system based on cut-offs for CD4 cell counts and the viral load, and conducted survival analyses for time to AIDS. The cut-offs used were based on CD4 cell count and viral load thresholds at which one might consider initiation of therapy. In the risk scoring systems, the cut-offs for CD4 cell counts were at 200, 350 and 450 cells/mm3 and for the viral load it was at 55,000 copies/ml ”

“ Of broad relevance, using HIV as a model system, we outline a series of analyses that might have application to other diseases when assessing whether genetic information can be used to improve the clinical care of patients afflicted with these diseases. ”

“ Remarkably, the CART approach also showed that the CCL3L1-CCR5 GRGs assist in AIDS prognosis mainly during early-stage disease, such as when baseline CD4 cell counts are greater than 453 cells/mm3, a CD4 cell count threshold that is well above the point at which ART is currently recommended. ”

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“ These findings have broader translational value as they indicate that AIDS risk is an individual characteristic that might be estimated with an increased level of confidence if one also considers the genetic make-up of the host. ”

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