Drug Metabolism and Disposition Genes in Israeli HIV Patients: MDR1 and CYP3A4 Polymorphisms May Affect Susceptibility to HIV but Not the Course of the Disease.

Background: Some studies have suggested a relationship between different alleles of the multidrug resistance gene MDR1, and the course of HIV in treated or untreated patients (pts). It is controvertial whether polymorphisms alter the susceptibility to HIV infectivity. We therefore studied the C3435T polymorphism in MDR1, which may influence HIV. The normal allele has been associated with higher MDR1 activity than the polymorphic allele (Hitzl, 2001). We also studied the A to G polymorphism in the NFSE element of the promoter of the CYP3A4 gene, which metabolizes many important drugs.

Methods: 96 pts, of either Ethiopian (57) or Caucasian (39) ethnicity, and 276 controls of these ethnic groups were studied using PCR based techniques. MDR1 activity was analyzed on peripheral blood mononuclear cells of 65 pts using rhodamine extrusion. CD4 counts, clinical course and opportunistic infections were recorded at the Hadassah Hospital AIDS Center where all pts are followed. Our pts are highly compliant with medical therapy and followup. Statistical significance was determined using the Cochrane-Armitage Trends test.

Results: We found that the C allele of MDR1 C3435T was highly associated with being an HIV patient (p<0.0001) as compared to controls. The reverse was true for the T allele. This association was found for all patients and also separately for each ethnic group. To analyze if this polymorphism affects the course of HIV, we compared CD4 counts in the patients of both ethnic groups according to genotypes. CD4 counts did not differ according to MDR1 C3435T genotype. Furthermore, C3435T genotypes did not affect the change in CD4 count over time in treated pts. CD4 counts rose following antiretroviral therapy in all pts. Twenty-eight of the pts were positive for HIV infection but were not yet treated. In untreated pts, the TT patients had more severe CD4 deficiency over time compared to CC pts. Our sample size is small, but this concurs with the findings of Lee who found that increased MDR1 activity correlated with decreased viral production (Lee, CG, FASEB J, 2000). Rhodamine extrusion did not vary according to MDR1 C3435T genotype. Opportunistic infections were rare and unaffected by genotype. For the CYP3A4 promoter polymorphism, we found a significantly increased probability of being infected with HIV (p<0.0001) with the presence of the C allele, both in heterozygotes and in homozygotes. There were significantly fewer T alleles among the controls as compared to HIV pts. However when analyzed by ethnic group, this association was only found to be significant for Ethiopians and not for Caucasians (Ethiopians: p< 0.0232 compared to p=0.44). There were no differences found in CD4 count, in treated or untreated patients, or in opportunistic infections according to CYP3A4 genotype.

Conclusions: We conclude that for Israeli patients (Ethiopians and Caucasians), susceptibility to HIV infection may be altered according to MDR1 genotype. The C allele was highly associated with infection with HIV for both ethnic groups, as compared to normal controls. For Ethiopians, the CYP3A4 genotype may influence the predisposition to HIV infection (the C allele being associated with being a patient as compared to controls). However, the course of the disease and unsorted lymphocyte MDR1 activity were not influenced by the polymorphisms which we studied.