Inhibition of Human Immunodeficiency Virus Type 1 Entry by a Keggin Polyoxometalate

Wang, Xiaoli; Wang, Jiao; Zhang, Wenmei; Li, Boye; Zhu, Ying; Hu, Qin; Yang, Yishu; Zhang, Xiaoguang; Yan, Hong; Zeng, Yi

PT-1 was evaluated for antiviral activity on 15 laboratory strains using TZM-bl cells or T cells. The corresponding half-maximal inhibitory concentration (IC50) values are summarized in Table 1 . Considerable variability in the susceptibilities of virus subtypes to PT-1 was observed, with PT-1 inhibited subtypes B at a relatively higher potency and showed less sensitivity towards subtype C and A in TZM-bl cells. In MT4 cells, the replication of the wide-type virus was significantly inhibited by PT-1 at IC50 ranging from 0.47 to 1.56 µM. To confirm the inhibition in primary T cells, PT-1 was tested using HIV-1 NL4-3 and PBMCs from three healthy donors, respectively. PT-1 exhibited a strong inhibitory effect on PBMCs with IC50 and IC90 ( Figure 1A and Table S1 ), The HIV-1 nucleoside reverse transcriptase inhibitor AZT, serving as a positive control, exhibited broad inhibitory activities against all tested viruses ( Figure 1B ). In addition to its remarkable high potency, PT-1 showed low cytotoxicity in TZM-bl, MT4 cells and PBMCs, even at a concentration that was 100-fold higher than the effective dose ( Figure 1C and Table 1 ). No significant changes in the percentage of early and late apoptotic cells were seen in PBMCs and MT4 cells after PT-1 treatment ( Figure 1D and Figure S1 ). Furthermore, the genotoxic effect of PT-1 was monitored using mouse bone marrow micronucleus tests ( Figure 1E , Table S2 ), and the data showed that PT-1 at doses up to 1800 mg/kg resulted in no mortality and bone marrow toxicity. Moreover, a serial of PT-1 organic analogs with amino acid modification were tested using TZM-bl assay, and they all exhibited potent anti-HIV activity ( Figure S2 ). Thus, PT-1 was a powerful inhibitor of HIV-1 infection. TI, therapeutic index. ND, not determined.