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Abstract
Fullerene derivatives with hydrophilic substituents have been shown to exhibit a range of biological activities, including antiviral ones. For a long time, the anti-HIV activity of fullerene derivatives was believed to be due to their binding into the hydrophobic pocket of HIV-1 protease, thereby blocking its activity. Recent work, however, brought new evidence of a novel, protease-independent mechanism of fullerene derivatives’ action. We studied in more detail the mechanism of the anti-HIV-1 activity of N,N-dimethyl[70]fulleropyrrolidinium iodide fullerene derivatives. By using a combination of in vitro and cell-based approaches, we showed that these C70 derivatives inhibited neither HIV-1 protease nor HIV-1 maturation. Instead, our data indicate effects of fullerene C70 derivatives on viral genomic RNA packaging and HIV-1 cDNA synthesis during reverse transcription—without impairing reverse transcriptase activity though. Molecularly, this could be explained by a strong binding affinity of these fullerene derivatives to HIV-1 nucleocapsid domain, preventing its proper interaction with viral genomic RNA, thereby blocking reverse transcription and HIV-1 infectivity. Moreover, the fullerene derivatives’ oxidative activity and fluorescence quenching, which could be one of the reasons for the inconsistency among reported anti-HIV-1 mechanisms, are discussed herein.
Highlights
During its replication cycle, HIV-1 forms two distinct particles, immature and mature ones
The virus was produced upon transfection of HEK 293 cells with appropriate vectors in the presence of the fullerene derivatives, and the released HIV-1 particles were used for infection of fresh cells
In agreement with published data [35,36], we did not observe any effect of these fullerenes on the early phase of HIV-1 infection—i.e., when these compounds were added to the HEK 293 cells infected with normalized amounts of reporter HIV-1 (Figure 1c)
Summary
HIV-1 forms two distinct particles, immature and mature ones. An immature HIV-1 particle is formed by Gag polyprotein precursors consisting of four structural domains—matrix (MA, p17), capsid (CA, p24), nucleocapsid (NC), and p6—and two short spacer peptide sequences linking CA with NC (SP1) and NC with p6 (SP2). The assembly of the immature HIV-1 particle is driven mainly by interactions among CA domains of Gag polyprotein triggered by the NC–viral genomic RNA scaffold. The transition to a mature, fully infectious HIV-1 particle is triggered by activation of the virus-encoded protease (PR), which cleaves Gag polyproteins into individual viral proteins. The mature HIV-1 hexameric lattice, formed approximately by 250 CA hexamers and 12 pentamers [1,2,3,4], encloses and protects viral genomic RNA, complexed to NC. The insertion of CA pentamers allows the formation of a closed conical core, characteristic of HIV-1 [2,5]
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