Lack of effective strategies for killing cells latently infected with HIV-1 limits the eradication of AIDS. Unfortunately, current antiretroviral inhibitors are designed to target virus production but not latent infection. Interestingly, some non-nucleoside reverse transcriptase inhibitors (NNRTIs) have shown off-design effects, specifically, premature activation of HIV-1 protease (PR) within virus-infected cells that induces apoptosis. Here, we analyze an equilibrium model of HIV-1 reverse transcriptase (RT) binding to NNRTIs to understand the optimal binding characteristics that enhance RT dimerization within embedded GagPol dimers. This would allow NNRTIs to act as PR autoactivation enhancers (PAEs). We compute that ∼700-fold enhancement is theoretically possible by PAEs. Both a strong drug-dimer binding affinity (KD12 < 100 nM) and relatively weaker drug-monomer affinity (KD2/KD12 > 10) are required for significant enhancement (∼50-fold or more) relative to the drug-free dimer concentration within a drug concentration limit of 10 μM. Our approach rationalizes the observed effects of efavirenz on premature activation of PR and may be useful to guide the design of suitable drug candidates and their optimal dosage regimens for this therapy class.
Keywords: HIV-1 eradication therapy; drug binding thermodynamics; mathematical modeling.