Influence of polymorphisms within the CX3CR1 and MDR-1 genes on initial antiretroviral therapy response

Objective: Single nucleotide polymorphisms (SNP) in the genes encoding the human CX 3 CR1 chemokine receptor and the P-glycoprotein multidrug transporter have been associated with accelerated disease progression in untreated individuals and implicated in therapeutic response, respectively. This retrospective study assessed the influence of SNP in the CX 3 CR1 and MDR-1 genes on initial virological and immunological response in 461 HIV-infected, antiretroviral-naive individuals initiating antiretroviral therapy in British Columbia, Canada. Methods: CX 3 CR1 and MDR-1 SNP were determined by PCR amplification of human DNA from plasma, followed by DNA sequencing. Time to virological success [time to HIV plasma viral load (pVL) ≤ 500 copies/ml], virological failure (subsequent time to the second of two consecutive pVL ≥ 500) and immunological failure (time to the second consecutive CD4 cell count below baseline) were analyzed by Kaplan-Meier methods. Results: Frequencies of CX 3 CR1 amino acid haplotypes were 249V 280T (0.75), 2491 280M (0.15), and 2491 280T (0.1). Frequencies of MDR-1 nucleotide polymorphisms were 3435C (0.47) and 3435T (0.53). There was no effect detected for SNP in CX 3 CR1 or MDR-1 on time to virological success, nor of CX 3 CR1 and MDR-1 SNP on time to virological and immunological failure, respectively (P>0.1). There was a trend to earlier virological failure in the MDR-1 3435C/C genotype group (P = 0.07), and a statistically significant trend to earlier immunological failure in individuals with the CX 3 CR1 2491 polymorphism (P= 0.02). These remained significant after correcting for baseline age, sex, pVL, CD4 cell count, type of therapy, and adherence (P ≤ 0.05). Conclusion: Polymorphisms in MDR-1 and CX 3 CR1 may be associated with accelerated virological and immunological therapy failure, respectively.