Fig 1.
Chemical structures of the HIV-1 maturation inhibitors discussed in this study.
The structure of GSK232 was adopted from Johnson et al. (70). Bevirimat was adopted from PubChem CID entry 457928. GSK795 was based on the structure reported by Nowicka-Sans et al. (49). GSK254 was adopted from Dicker at al. (45). All structures were drawn in Marvin JS version 21.14.0 (ChemAxon Int., International; available at https://chem.nlm.nih.gov/chemidplus).
Table 1.
Susceptibility of HIV-1, HIV-2, and SIV isolates to GSK2838232 in spreading infections of CEMss cells.
Fig 2.
Dose-response plots from spreading-infection assays of GSK232 antiviral activity, which were performed in CEMss cells.
Data points indicate the amount of infectious virus produced in GSK232-treated cultures relative to the amount produced in cultures that received solvent only (no-drug controls). Each point is the mean of four cultures that were maintained in parallel. Error bars indicate ±1 SD and, when not visible, are smaller than the symbols. IC50 values were calculated for the HIV-1 isolates using a four-parameter regression model in GraphPad Prism 6.0 as described in the Materials and Methods; the regression curves are shown as dashed lines. R2 values are also shown as calculated in Prism.
Table 2.
Susceptibility of HIV-1, HIV-2, and SIV isolates to GSK2838232 in a single cycle of viral replication.
Fig 3.
Effects of amino acid changes in the CA/SP1 site of HIV-2ROD9 on GSK232 susceptibility.
A Alignment of HIV-1 and HIV-2 Gag CA/SP1 amino acid sequences. The top line (HIV-1 M/B) shows the consensus sequence from an analysis of 1295 HIV-1 group M subtype B isolates. This sequence is available at https://www.hiv.lanl.gov/content/sequence/NEWALIGN/align.html, using the following settings – Alignment type: consensus/ancestral, Organism: HIV-1/SIVcpz, Region: GAG, Subtype: M group without recombinants, Year: 2021. The corresponding sequence encoded by the pROD9 molecular clone of HIV-2, and a variant of pROD9 (plasmid clone M3) in which the bases encoding the P2, P1, and P4´ sites of CA/SP1 were altered via site-directed mutagenesis is also shown. All of the group M HIV-1 isolates (including molecular clones) that were tested in this study encode CA/SP1 sequences that are identical to the one shown for HIV-1 M/B except for HIV-192UG029, which contains an isoleucine at the P2 position (see Materials & methods for sequence sources). HIV-2ST, HIV-27312A, SIVmac239, SIVmac251, are identical to that of HIV-2ROD9 in the region shown; SIVagm.sab-2 contains a threonine at the c-terminal–most site in the alignment. Sequence information was unavailable for HIV-1BFC01 and HIV-2CDC310319 in the region of interest. B Dose-response curves from single-cycle assays with HIV-2ROD9 mutant M3 and HIV-1NL4-3. Each point is the mean of four cultures that were maintained in parallel. Error bars indicate ±1 SD and, when not visible, are smaller than the symbols. IC50 values were calculated for the HIV-1 isolates using a four-parameter regression model in GraphPad Prism 6.0 as described in the Materials & methods; the regression curves are shown as dashed lines. R2 values were also calculated in Prism. IC50 values for the data plotted in this figure are 2.7 nM for HIV-2ROD9 M3 (R2, 0.98) and 3.2 nM for HIV-1NL4-3 (R2, 0.97).