Abstract
Human immunodeficiency virus (HIV-1) entry is initiated by the binding between the viral envelope glycoprotein gp120 and the host receptor CD4, and followed by reduction of structural disulfides of gp120 and CD4. The host thioredoxin-1 (Trx1) efficiently reduces disulfides of gp120 and CD4 in vitro, and recently CD4-dependent HIV-1 entry was shown to be inhibited by anti-Trx1-antibodies, indicating a central role for Trx1. 1-methylpropyl-2-imidazolyl disulfide (PX-12) is a reversible inhibitor of the Trx1 system that may also cause a slow irreversible thioalkylation of Trx1. It was developed as an antitumor agent, however, the current study aimed to determine if it also has an anti-HIV-1 effect. We show that PX-12 has anti-HIV-1(IIIB) activity in TZM-bl cells, in fact, no virus was detected inside the cells in the presence of 10 µM PX-12. Moreover, PX-12 inhibited the enzymatic activity of Trx1 and the Trx1-dependent disulfide reduction of gp120. Microtubule polymerization and formation of acetylated microtubules were also inhibited, activities shown to be required for HIV-1 life cycle propagation. In conclusion, our data strengthens the notion that the early steps of the HIV-1 life cycle depends on the Trx1 system and indicate that the Trx1 system may be a rational drug target for HIV-1 treatment.
Highlights
A large body of evidence has indicated that HIV-1 entry is dependent on redox control
The cytotoxicity of PX-12 on TZM-bl cells was studied by exposing the cells to different concentrations of PX-12 in exactly the same way the cells are exposed to PX-12 in the infectivity assay protocol
In a previous study we observed that organotellurium compounds that interfere with oxidoreductase activity inhibited both HIV-1 and HIV-2 replication by targeting an early event in the viral replication cycle (Reiser et al, 2016)
Summary
A large body of evidence has indicated that HIV-1 entry is dependent on redox control (reviewed in[6]). Agents that inhibit thiol/disulfide exchange reactions have been shown to suppress HIV-1 viral entry suggesting that redox may be a rational target for HIV-1 treatment[8,9,12,13,14,15,16]. A recent study indicated that specific inhibition of Trx[1], using anti-Trx[1] antibodies, inhibited HIV-1 entry by >80%, suggesting that Trx[1] may have a central role in HIV-1 entry[13]. PX-12 has broad effects by inhibiting both TrxR1 and Trx[1] as a disulfide reductase as well as inactivating Trx[1] by irreversibel thioalkylation which blocks its activity as a disulfide reductase of proteins It is not known whether PX-12 has an effect by interfering with the life cycle of HIV-1. Our data indicate that Trx[1] may have a central role in the early steps of the HIV-1 life cycle and that Trx[1] may be a rational drug target for HIV-1 treatment
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