Preclinical virology profiles of the HIV-1 capsid inhibitors VH4004280 and VH4011499

With its high degree of conservation and critical role in multiple steps of the HIV-1 life cycle, the HIV-1 capsid protein presents an attractive therapeutic target. Herein, the virologic properties of the HIV-1 capsid inhibitors VH4004280 (VH-280) and VH4011499 (VH-499), including potency, mechanisms of action, and resistance profiles, are described. VH-280 and VH-499 inhibited panels of HIV-1 laboratory strains and viruses containing capsid sequences from clinical isolates with half-maximal effective concentrations in the picomolar range. Time-of-addition experiments determined that the primary block to HIV-1 replication occurred after nuclear import and before integration; however, measurements of replication intermediates by quantitative polymerase chain reaction, Gag degradation, p24 release, and virion morphology by cryo-electron microscopy indicate that VH-280 and VH-499 also block nuclear import, total reverse transcript production, integration, virion assembly, and maturation. In vitro Resistance Selection identified Q67H, A105E, T107D/N, and combinations of these substitutions as conferring 6- to >5,000-fold reductions in susceptibility to both compounds. Certain resistance-associated mutations selected by Other capsid inhibitors also reduced susceptibility. Overall, the preclinical virology profiles and Other drug-like properties support the potential of VH-280 and VH-499 as long-acting agents for HIV-1 treatment and prevention.