Preventing HIV Infection by Binding LEDGF with an Intracellular Antibody that Mimics HIV Integrase

Preventing the protein‐protein interaction of the cellular chromatin binding protein LEDGF and HIV integrase is an important strategy for alternative anti‐viral treatment for AIDS. While potent small molecules capable of performing this function have been difficult to develop, intracellular antibody fragments can readily be designed to perform with high affinity binding in vivo. We have isolated a single VH domain that binds to LEDGF and blocks the binding of HIV integrase to LEDGF. The crystal structure of the LEDGF‐VH complex reveals a remarkably similar region of the binding for the single domain antibody fragment and HIV integrase on LEDGF as a mimic of integrase. In cell assays, the intracellular domain antibody inhibits virus capsid p24 protein production after HIV virus infection into CD4‐expressing target T cells. Therefore, blocking the HIV interaction surface of cellular LEDGF with the potent antibody fragment macromolecule is a way to prevent HIV spread in infected patients. This antibody fragment is available for intracellular vaccination approaches in combating HIV‐based disease by inhibiting retroviral incorporation into the genome of infected cells in HIV‐positive patients.