Lack of activity of HIV-1 integrase strand-transfer inhibitors on recombinase activating gene (RAG) activity at clinically relevant concentrations

Abstract

INSTIs are a crucial component of antiretroviral treatments for HIV-1 infection. This study provides a careful and thorough analysis of the impact of approved INSTIs on recombinase activating gene (RAG1 and RAG2) activity, which plays a pivotal role in the adaptive immune system. The concentrations tested were derived from several clinical studies and accounted for the maximum free fraction of the drug available in patients. This approach ensures that our findings are directly applicable to clinical scenarios by providing meaningful insights into the potential drug side effects in patients. We developed biochemical and cellular assays to measure the impact of INSTIs on RAG activity. All tested INSTIs did not inhibit RAG at supratherapeutic concentrations in the RAG1/RAG2 biochemical cleavage and cellular V(D)J recombination assays. Our assessment supports the continued use of INSTIs in HIV-1 treatments without concern for adverse effects.