Antiviral Activity of Bictegravir and Cabotegravir against Integrase Inhibitor-Resistant SIVmac239 and HIV-1

Abstract

Animal models are essential to study novel antiretroviral drugs, resistance-associated mutations (RAMs), and treatment strategies. Bictegravir (BIC) is a novel potent integrase strand transfer inhibitor (INSTI) that has shown promising results against HIV-1 infection in vitro and in vivo and against clinical isolates with resistance against INSTIs. BIC has a higher genetic barrier to the development of resistance than two clinically approved INSTIs, termed raltegravir and elvitegravir. Another clinically approved INSTI, dolutegravir (DTG) also possesses a high genetic barrier to resistance, while a fourth compound, termed cabotegravir (CAB), is currently in late phases of clinical development. Here we report the susceptibilities of simian immunodeficiency virus (SIV) and HIV-1 integrase (IN) mutants containing various RAMs to BIC, CAB, and DTG. BIC potently inhibited SIV and HIV-1 in single cycle infection with 50% effective concentrations (EC₅₀s) in the low nM range. In single cycle SIV infections, none of the E92Q, T97A, Y143R, or N155H substitutions had a significant effect on susceptibility to BIC (≤4-fold increase in EC₅₀), whereas G118R and R263K conferred ∼14-fold and ∼6-fold increases in EC₅₀, respectively. In both single and multiple rounds of HIV-1 infections, BIC remained active against the Y143R, N155H, R263K, R263K/M50I, and R263K/E138K mutants (≤4-fold increase in EC₅₀). In multiple rounds of infection, the G140S/Q148H combination of substitutions decreased HIV-1 susceptibility to BIC 4.8-fold compared to 16.8- and 7.4-fold for CAB and DTG, respectively. BIC possesses an excellent resistance profile in regard to HIV and SIV and could be useful in nonhuman primate models of HIV infection.

Keywords: HIV; SIV; bictegravir; cabotegravir; dolutegravir; integrase; integrase strand transfer inhibitors; resistance.

FIG 1

Resistance profiles of BIC, CAB, and DTG against SIVmac239 IN mutations. BIC, CAB, and DTG were each tested in TZM-bl cells infected with SIVmac239 WT or IN mutants in order to determine the effects of mutations on EC₅₀s. Each bar represents the mean fold change in EC₅₀ derived from three or more independent experiments in comparison with WT virus. Error bars represent standard errors. An asterisk (*) indicates statistically significant difference from WT virus. Statistical significance was calculated using a one-sample two-tailed t test with a statistical cutoff of P ≤ 0.05 versus WT.

FIG 2

Resistance profiles of BIC, CAB, and DTG against HIV-1 pNL4.3 IN mutations. BIC, CAB, and DTG were each tested in TZM-bl cells infected with HIV-1 pNL4.3 WT or IN mutants in order to determine the effects of mutations on EC₅₀. Each bar represents the mean fold change in EC₅₀ derived from three or more independent experiments in comparison with WT virus. Error bars represent standard errors. An asterisk (*) indicates statistically significant difference from WT virus. Statistical significance was calculated using a one-sample two-tailed t test with a statistical cutoff of P ≤ 0.05 versus WT.