479 Influence of MDR1 on CD4+ Cell Permissiveness to HIV-1 Infection G. Bleiber*, C. Suarez, R. Martinez, J. Fellay., C. Marzolini, A. Telenti CHUV Lausanne, Switzerland
Background: MDR1 encodes the ABC transporter P-glycoprotein (PGP). Recent reports indicate that overexpression of PGP leads to a reduction in the infectivity and cellular permissiveness in vitro by interference with viral fusion, and possibly viral release. However, these experiments use in vitro models characterized by non-physiological over-expression of transfected MDR1, and the observations are yet to be evaluated under physiological conditions and in the in vivo setting. Allelic variants in exon 21 and 26 have been associated with differences in expression and/or function of MDR1/PGP, and thus could lead to differences in natural progression of HIV-1 infection.
Methods: Purified CD4+ cells from 100 healthy blood donors were infected in vitro using R5-tropic NL4-3 (BaL env). p24 production at day 7 post-infection was used to characterize the degree of cellular permissiveness to infection. DNA was genotyped at MDR1 G2677T and C3435T, as well as for CCR5, CCR2, and CX3CR1 allelic variants by using TaqMan allelic discrimination. MDR1 expression was assessed by mRNA quantification. In addition, the association of MDR1 variants with specific patterns of disease evolution were investigated in 700 HIV-1 infected individuals.
Results: MDR1 exon 21 (2677 G/T) and exon 26 (3435 C/T) alleles are genetically linked. Mean±SEM p24 values (pg/ml at day 7) for position 3435 were: 66850±10510 (CC), 84230±7256 (CT), 83310±12130 (TT), (p=0.49), and for position 2677 were: 89130±11020 (GG), 85440±8149 (GT), 81320±10010 (TT), (p=0.96). No correlation was identified between MDR1 expression and permissiveness (r2 <0.01, p=0.71). In multivariate analysis with CCR5, CCR2 and CX3CR1 as covariates, MDR1 polymorphisms were not associated with differences in cell permissiveness. Preliminary analysis of a human cohort of HIV-1 infected individuals did not identify differences in disease progression for the various alleles.
Conclusions: Non-physiological expression of MDR1 is reported to modify HIV-1 permissiveness in vitro. In contrast, under physiological conditions, MDR1 expression in purified CD4+ cells is not associated with differences in cell permissiveness to HIV infection. In addition, alleles associated with differences in MDR1 expression are not related to differences in susceptibility to HIV-1 in vitro, or in vivo.
