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.

Gut-derived bacterial toxins impair memory CD4+ T cell mitochondrial function in HIV-1 infection

“…Thus, PCS indeed has a pleiotropic effect; however, PCS uses the cell surface organic anion transporter 1 (OAT-1) and OAT-3 receptors to enter cells (54). It has been demonstrated (55,56) and validated by our group (data not shown) that OAT-1 and OAT-3 receptors are not expressed on PBMCs in vitro and as shown in Supplemental Figure 8, PCS impedes all immune cells. In addition, PCS was found enriched in memory CD4 + T cell lysates of INRs compared with findings among IRs or HCs (Figure 1A).…”

A Non-natural Nucleoside with Combined Therapeutic and Diagnostic Activities against Leukemia

“…The major recognition element for efficient transport is the presence of a natural (deoxy)sugar moiety . Transport activity is highly sensitive to the correct sugar conformation as nucleoside analogues such as AZT (zidovudine) and ddC (zalcitabine) that lack a 3′-hydroxyl group show poor cellular uptake. , As such, the presence of an unmodified deoxyribose group on 5-NIdR and 3-Eth-5-NIdR may facilitate their cellular transport and provide an advantage over conventional nucleoside analogues such as fludarabine and gemcitabine that use modified sugar moieties to inhibit DNA synthesis. The presence of a correct deoxyribose moiety on 5-NIdR and 3-Eth-5-NIdR may also facilitate their conversion to the triphosphate form that is required for incorporation into nucleic acid .…”