Capsid-Targeting Biologic Achieves Broad HIV-1 Neutralization with a High Barrier to Resistance

Antiretroviral therapy (ART) has proven effective in suppressing HIV-1 replication, but further development of HIV-1 inhibitors is continually driven by the challenge of drug resistance and viral adaptation. The HIV-1 capsid is a promising target for treatment due to its high sequence conservation as well as its crucial role in the viral life cycle. Recently, we have developed a novel capsid-targeting biologic that prevents HIV-1 replication by efficient degradation of newly synthesized capsid. Here, we have investigated the sensitivity to viral escape as well as the breadth of this biologic against HIV-1 subtypes. The capsid-targeting biologic efficiently blocked replication of different primary HIV-1 isolates, and continuous exposure of these viruses to the biologic resulted in viral breakthrough of two out of ten primary HIV-1 isolates tested. Notably, the breakthrough variants did not have amino acid changes in the nanobody epitope but primarily in the matrix region. The breakthrough variants remained sensitive to the biologic albeit to a lesser extent. In the absence of the biologic, breakthrough variants showed increased replication kinetics when compared to their parental virus, suggesting that adaption to the biologic is likely due to the increased viral production and that the target area of the biologic is too conserved for actual escape. This is further underscored by the broad specificity of the biologic as importantly the biologic blocked infection of different HIV-1 subtypes that occur worldwide (A, B, C, D, CRF01_AE, CRF02_AG). These results demonstrate the broad neutralization potential of anti-capsid biologics with a high barrier to resistance, making capsid-targeting inhibitors important for novel antiretroviral drug strategies worldwide.