Effect of Phosphonated Carbocyclic 2′-Oxa-3′-Aza-Nucleoside on Human T-Cell Leukemia Virus Type 1 Infection In Vitro

摘要

There is currently little research and development of new compounds with specific anti-human T-cell leukemia virus type 1 (HTLV-1) activity. The few antiretrovirals that have been tested against HTLV-1 in vitro have already been developed into anti-human immunodeficiency virus (HIV) drugs. Here, we show the effects of a newly synthesized family of phosphonated nucleoside compounds, phosphonated carbocyclic 2′-oxa-3′-aza-nucleosides (PCOANs), on HTLV-1 infection in vitro. To ascertain the anti-HTLV-1 activity of PCOANs, peripheral blood mononuclear cells from healthy donors were infected in vitro by coculture with an HTLV-1 donor cell line in the presence of three prototype PCOAN compounds. PCOANs were able to completely inhibit HTLV-1 infection in vitro at a concentration of 1 μM, similar to what has been observed for tenofovir and azidothymidine. Treatment with PCOANs was associated with inhibited growth of HTLV-1-infected cells, and their effects were 100 to 200 times more potent than that of tenofovir. The mechanisms involved in the anti-HTLV-1 effects of PCOANs can mainly be ascribed to their capacity to inhibit HTLV-1 reverse transcriptase activity, as ascertained by means of a cell-free assay. PCOANs caused little reduction in proliferation or induction of apoptotic cell death of uninfected cells, showing toxicity levels similar to tenofovir and lower than azidothymidine. Overall, these results indicate that the family of PCOANs includes potential candidate compounds for long-lasting control of HTLV-1 infection.