Pharmacogenomics, the study of genetic predisposition to medicines, is an emerging area of medical research. Its application in HIV medicine is still in its infancy. A recent study published in the Journal of Infectious Diseases suggests that caution is required when speculating about the effects of host genetics on drug absorption and disease progression. In the words of Dr Amalio Telenti of the University of Lausanne, Switzerland, “Only 30% of published genetic associations are true, and the first to publish is usually the strongest.”
P-glycoprotein and MDR-1
P-glycoprotein (P-gp) is a membrane-bound drug transport molecule that protects cells from toxic intruders such as cancer chemotherapies and HIV antiretrovirals by pumping them out of cells. But by lowering the concentration of protease inhibitors within cells, P-gp can hinder antiviral efficacy. Some people have different versions of the MDR1 (for multi-drug resistance) gene that produces P-gp, and different combinations, or alleles, of these MDR1 genes will produce different amounts of P-gp. A report from the Swiss HIV Cohort published two years ago found an association between the genetic predisposition for having less P-gp and greater rises in CD4 counts within six months of starting an antiretroviral regimen containing nelfinavir or efavirenz. The theory is that people who express less MDR1 have less P-gp, which means that their drugs stay in their cells longer.
But other reports have suggested that P-gp, even in the absence of therapy, might also play a role in how susceptible cells are to becoming infected with HIV. A few laboratory-based experiments have shown a dramatic decrease in viral replication in cells that produced P-gp abundantly; protection that was lost when P-gp blockers were added. One theory holds that P-gp may be interfering with various lipid molecules on the cell surface that are needed to assist with HIV fusion and entry. But these reports have been controversial, partly because some of the cells studied expressed over 1000 times as much P-gp as T-cells do. A new report by Gabriela Bleiber, a researcher at the University Hospital of Lausanne and a member of the Swiss Cohort team, now casts doubt on these previous findings with results from an experiment using T-cells with normal levels of P-gp.
She assembled a collection of purified T-cells from 128 HIV-negative persons. This provided a population of test cells with a cross-section of the different MDR1 alleles. The cells of the uninfected donors were genotyped for two particular changes, or single nucleotide polymorphisms (SNPs), within two different sections of the MDR1 gene. As expected, Bleiber found a 2- to 3-fold difference in the amount of MDR1 mRNA expressed by the cells from individuals with the various alleles. Although this new study didn’t measure P-gp levels directly, the earlier report from the Swiss Cohort had established a good relationship between MDR1 expression and the presence of actual P-gp on the cell surface.
The T-cells were then infected with a laboratory strain of HIV and each was characterized for its permissiveness to infection by measuring the amount of the HIV p24 protein present at days 5 and 7. When the MDR1 alleles of the donors were correlated with the results of the permissiveness assay, there was no evident association between P-gp levels and a cell’s susceptibility to HIV infection.
MDR-1 and T-cell depletion: is there any connection?
To try to further resolve the controversy over the relevance of the MDR1 alleles in untreated HIV-positive people, Bleiber and colleagues also genotyped stored blood samples from 411 treatment-naïve members of the Swiss HIV Cohort. Then they correlated those findings with an analysis of retrospective CD4 data to establish “the trajectory of T-cell depletion” in each individual and estimate his or her rate of disease progression. Overall, on average, it took 3.68 years for CD4 cell counts to decline from 500 to 200 in the cohort. Although there was some variation when the data were analysed by the different alleles - one was associated with a slightly faster rate of progression (3.5 years) and another with a slightly slower rate (3.76 years) - confidence intervals were wide and none of the differences were statistically significant. While the authors concede that there may be a small effect of MDR1 expression on disease progression that this study cannot detect, they do not find such an effect either in their laboratory-based system or in their analysis of disease progression in the Swiss Cohort.
Further information on this website
Genes affect drug levels but genetic tests still far away - News story, January 2002.
Reference
Bleiber G, May M, Suarez C, et al. MDR1 genetic polymorphism does not modify either cell permissiveness or disease progression before treatment. J Inf Dis, 189;583-586, 2004.