3′-Azido-2′,3′-Dideoxythymidine (Zidovudine) Uptake Mechanisms in T Lymphocytes

Abstract

The nucleoside reverse transcriptase inhibitors (NRTIs) make up a family of antiretroviral drugs widely used in the treatment of HIV-1 infection. Human concentrative nucleoside transporters and equilibrative nucleoside transporters, encoded by SLC28 and SLC29 gene families, respectively, are known to be involved in the uptake of a variety of nucleoside analogues used in anticancer treatment. We therefore examined whether SLC28- and SLC29-encoded proteins contribute to the entry of these NRTIs into the human leukaemic T-cell line Molt-4. Cis-inhibition experiments demonstrated that nucleoside transporters have a negligible role in antiviral drug uptake. Moreover, the previously identified 3′-azido-2′,3′-dideoxythymidine (zidovudine; AZT) carriers, organic anion transporters (organic anion transporter [hOATs], members of the SLC22 gene family) have not been detected in T cells, either functionally or at the mRNA level, thus ruling out a role for hOATs in antiviral drug uptake in these cells. Nevertheless, the data provided here argue against the hypothesis of simple diffusion across the plasma membrane as the unique mechanism of AZT uptake. Actually, this pyrimidine derivative seems to have a temperature-sensitive route of entrance, a finding that, along with the evidence that, AZT inhibits its own uptake and its transport into phytohaemagglutinin-stimulated peripheral blood mononuclear cells is upregulated, strongly support the idea that AZT uptake into T-cells is associated with a mediated and regulated, transport mechanism.