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 CX3CR1 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 CX3CR1 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
CX3CR1 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) < or = 500 copies/ml], virological failure (subsequent time to the second of two consecutive pVL > or = 500) and immunological failure (time to the second consecutive CD4 cell count below baseline) were analyzed by Kaplan-Meier methods.


RESULTS
Frequencies of CX3CR1 amino acid haplotypes were 249V 280T (0.75), 249I 280M (0.15), and 249I 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 CX3CR1 or MDR-1 on time to virological success, nor of CX3CR1 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 CX3CR1 249I polymorphism ( P = 0.02). These remained significant after correcting for baseline age, sex, pVL, CD4 cell count, type of therapy, and adherence ( P < or = 0.05).


CONCLUSIONS
Polymorphisms in MDR-1 and CX3CR1 may be associated with accelerated virological and immunological therapy failure, respectively.
Brumme
Zabrina L
ZL
B.C. Centre for Excellence in HIV/AIDS, St. Paul's Hospital, Vancouver, Canada.
Dong
Winnie W Y
WW
Chan
Keith J
KJ
Hogg
Robert S
RS
Montaner
Julio S G
JS
O'Shaughnessy
Michael V
MV
Harrigan
P Richard
PR
D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D000073883:CX3C Chemokine Receptor 1; D005260:Female; D005787:Gene Frequency; D019450:Genes, MDR / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000502:physiology; D006239:Haplotypes; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide; D019707:Receptors, Chemokine / Q000235:genetics*; D012189:Retrospective Studies; D017211:Treatment Failure; D019562:Viral Load
D019380:Anti-HIV Agents; D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D008565:Membrane Proteins; D019707:Receptors, Chemokine