CYP1A1 genotype modifies the impact of smoking on effectiveness of HAART among women.
We have recently shown that cigarette smoking is associated with lesser responses to potent antiretroviral therapies. Certain Cytochrome P-450 enzymes activate compounds derived from tobacco smoke into toxic forms that may promote HIV-1 gene expression through promotion of DNA-adduct formation by the oxidation of chemical constituents of cigarette smoke, such as polyaromatic hydrocarbons and dioxins. To explore the association between environmental and genetic factors to viral replication in women who smoke and receive highly active anti-retroviral therapy (HAART), we assessed the impact of polymorphisms in a panel of four Cytochrome P-450 genes (CYP1A1, CYP2A6, CYP2D6, and CYP2E1) and two Glutathione S-transferase genes (GSTM1 and GSST1) in 924 participants of the Women's Interagency HIV Study (WIHS). Our findings showed that GSTM1 and GSST1 deletions were not associated with HAART effectiveness. By contrast, homozygosity for the CYP1A1-m1 polymorphism, was associated with impaired viral response to treatment among smokers (relative hazard (RH) = 0.54; 95% confidence interval = 0.31-0.94) after adjustment for pretreament viral load, CD4 count, age, hepatitis C infection, prior HAART therapy and race, although it had no effect among nonsmokers. We conclude that the association of the CPY1A1-m1 variant with a reduced response to HAART therapy in HIV infected smokers is consistent with this enzyme's role in the metabolic conversion of environmental toxins to DNA adducts, which may directly promote HIV-1 gene expression.
Feldman
David N
DN
Department of Pathology, University of Arizona College of Medicine, Tucson, AZ 85724, USA. dfeldman@email.arizona.edu
Feldman
Joseph G
JG
Greenblatt
Ruth
R
Anastos
Kathryn
K
Pearce
Leigh
L
Cohen
Mardge
M
Gange
Stephen
S
Leanza
Suzanne
S
Burk
Robbie
R
D019380:Anti-HIV Agents / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D015331:Cohort Studies; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D018736:DNA Adducts / Q000235:genetics; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D015870:Gene Expression; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015497:HIV-1; D006801:Humans; D053208:Kaplan-Meier Estimate; D008137:Longitudinal Studies; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D015995:Prevalence; D016016:Proportional Hazards Models; D012907:Smoking / Q000009:adverse effects / Q000235:genetics*; D016896:Treatment Outcome; D019562:Viral Load; D014779:Virus Replication
D019380:Anti-HIV Agents; D018736:DNA Adducts; D019363:Cytochrome P-450 CYP1A1; D005982:Glutathione Transferase