Specific genotype could increase resistance to HIV drug therapy

August 02, 2001

N.B. Please note that if you are outside North america, the embargo for LANCET press material is 0001 hours UK Time Friday 3rd August 2001.

A specific mutation of a gene which influences the expression of a glycoprotein transporter protein involved in the body's resistance to drugs and other toxins is detailed in a research letter in this week's issue of THE LANCET. Results of the study suggest that drug therapies used in treating HIV-1 infection (notably protease inhibitors ) may not be as effective in West African and African American ethnic groups compared with Caucasian populations.

The variability of P-glycoprotein expression between individuals is linked to a C3435T alteration of the human MDR1 gene. Concentration of P-glycoprotein in intestinal epithelial cells and in some lymphoid cells is substantially lower in people with the T/T genotype than those with the C/C genotype. Matthias Schwab and colleagues from Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany, compared allele frequencies of the C3435T polymorphism in random samples of west African, African American, Caucasian, and Japanese people. The investigators recorded a substantially higher frequency of the high-expression C/C genotype in West Africans and African Americans (142 of 172 [83%] and 25 of 41 [61%], respectively), than in caucasian people (139 of 537 [26%]).

Matthias Schwab comments: "The C/C genotype could be a factor restricting access of HIV-1 protease inhibitors to their major cellular target, the CD4+ T-lymphocytes and to other sanctuary sites of the virus such as brain and testis, which are known to express P-glycoprotein. Further studies are needed to clarify the mechanism by which the C3435T polymorphism leads to decreased P-glycoprotein expression and to define its role as a susceptibility factor for infectious diseases and drug treatment with P-glycoprotein substrates. These findings could affect use of drugs that are P-glycoprotein substrates (such as HIV-1 protease inhibitors and ciclosporin) in African populations."
Contact: Dr Matthias Schwab, Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376 Stuttgart, Germany; T)49-711-8101-3728 F) 49-711-85-92-95 E) matthias.schwab@ikp-stuttgart.de


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