Allele frequency of three functionally active polymorphisms of the MDR-1 gene in high-risk HIV-negative and HIV-positive Caucasians

Recent data suggest thatMDR-1expression may affect HIV-1 infectivity by modulating the immune response and its cellular permissiveness. We investigated whether three functionalMDR-1polymorphims (T-129C, G2677T/A, C3435T) were associated with the risk of infection in 137 Caucasians highly exposed to HIV (70 infected and 67 uninfected). There was no difference in allelic frequencies for eachMDR-1polymorphic site among both groups. This finding suggests that P-glycoprotein expression does not influence HIV-1 infectionper se. The human multidrug resistance (MDR)-1 gene encodes a transmembrane P-glycoprotein, which confers resistance to a number of structurally unrelated types of clinically useful drugs. This protein is found in various normal tissues, such as small and large intestine, adrenal, kidney, liver, and placenta. Furthermore, it is expressed in haematopoietic progenitor cells, lymphocytes, and macrophages in a development- and differention-specific manner [1]. The modulation of MDR-1 expression in these cell types can influence the activity and bioavailability of drugs. So far, 15 polymorphisms have been described in the human MDR-1 gene. Three of these mutations have been correlated with human expression levels and the function of P-glycoprotein. Point mutations in the MDR-1 promoter (T-129C) and exon 21 (G26677A,T) have been associated with significantly lower levels of placental P-glycoprotein expression [2]. The G←T and A transversions at position 2677 (codon 893) result in amino acid changes from Ala to Thr or Ser, respectively. A synonymous polymorphism in exon 26 (C3435T) of the MDR-1 gene has also been described in association with low P-glycoprotein expression in enterocytes [3], and peripheral blood mononuclear cells (PBMC) [4]. Individuals homozygous for this polymorphism (TT genotype) have significantly lower levels of duodenal and PBMC P-glycoprotein expression than wild-type homozygotes (CC genotype). As concentrations of P-glycoprotein determine the extent of drug absorption and tissue concentrations, genotype-related differences in digoxin [3] and antiretroviral drug (nelfinavir and efavirenz) [4] plasma levels were observed. Moreover, in the latter study [4], the C3435T polymorphism predicted immune recovery after the initiation of antiretroviral treatment. Patients with the TT genotype had a greater increase in CD4 T cell counts than patients with the CT or CC genotypes 6 months after starting therapy. In addition to the role of P-glycoprotein in response to treatment through pharmacokinetic modulation, this protein could affect the natural history of HIV-1 disease [5]. Overexpression of P-glycoprotein reduces the susceptibility of human CD4 T cells to infection with HIV-1 in vitro, by affecting viral fusion and possibly viral release [6]. P-glycoprotein function is significantly reduced in CD16 natural killer (NK) cells from HIV-positive patients compared with controls. This reduced function significantly correlates with decreased NK cytotoxicity observed in HIV-infected individuals [7]. Functionally defective P-glycoprotein expression in CD4 and CD8 T cells in HIV-1 infection appears to increase with disease progression [8]. P-glycoprotein expression may thus affect HIV-1 infectivity by modulating the immune response and cellular permissiveness to HIV. To our knowledge, the potential association between P-glycoprotein expression and host susceptibility to HIV-1 infection has never been explored. In the present study, we investigated whether MDR-1 polymorphisms affecting the expression and function of P-glycoprotein are associated with the risk of HIV-1 infection. The study population consisted of 137 Caucasians exposed to HIV [infected and uninfected; exposed uninfected (EU)] enrolled in prospective cohort studies in Montreal. We analysed the DNA samples of 70 individuals infected with HIV-1 by homosexual contact or injection drug use recruited during primary infection. We identified 67 EU exposed to HIV-1 homosexually or parenterally and from whom DNA samples were available from prospective studies on the basis of their continued seronegative status despite high-risk exposure to HIV-1. The DNA samples of the 67 HIV EU individuals were analysed as the control group (HIV negative). MDR-1 genotyping was carried out by polymerase chain reaction restriction fragment length polymorphism analysis as described previously [2]. Control subjects were also genotyped for the CCR-5 gene, and none were found to be homozygous for the 32-base pair (bp) deletion allele. The study was approved by ethics committees, and all participants gave written informed consent. Table 1 shows the allelic distribution of the three functional MDR-1 polymorphisms among HIV-infected and EU subjects. The overall MDR-1 allelic distribution was similar to that observed in other populations, with the exception of the mutant allele at position 129, which was slightly less prevalent (≅3%) in our sample population than in Japanese (8.3%) and German populations (11.8%) [2,3]. There was no difference in allelic frequencies for each MDR-1 polymorphic site among HIV-infected and EU subjects.Table 1: Allelic distribution of three MDR-1 single nucleotide polymorphisms among HIV-positive and HIV-exposed uninfected (HIV-negative) study subjects.Our study focused on a well-characterized group that was carefully assessed for exposure, and demonstrated that functional MDR-1 variants are not associated with the risk of HIV-1 infection. Because these genetic polymorphisms correlate with P-glycoprotein expression and function, this finding suggests that P-glycoprotein is not implicated in the mechanism of HIV-1 infection per se. However, we cannot rule out the possibility that other unknown functional MDR-1 polymorphisms might influence HIV-1 infectivity. Extensive screening of HIV-EU and infected cohorts revealed that homozygosity for the 32 bp deletion at the CCR-5 locus conferred significant protection against infection in homosexual individuals. This was not the case in our study because none of the EU individuals were homozygotes for this allele. In this study, no evidence was found to suggest that P-glycoprotein correlates with the risk of acquiring HIV-1 through homosexual contacts or injection drug use. However, in view of the potential effect of P- glycoprotein expression on the host immune response and viral production, further studies are needed to define the role of P-glycoprotein as a susceptibility factor for HIV disease progression.

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