Characterization of rare lens epithelium-derived growth factor/p75 genetic variants identified in HIV-1 long-term nonprogressors

Abstract

Lens epithelium-derived growth factor (LEDGF)/p75 is a cellular binding partner of HIV-1 integrase and a crucial cofactor for HIV-1 replication. Here, we study two LEDGF/p75 exonic variants I436S and T473I, identified in HIV-1 long-term nonprogressors, together with Q472L. In-vitro binding assays, cell culture complementation, and functional rescue. Binding affinities of wild-type, I436S, T473I, and Q472L LEDGF/p75 for HIV-1 integrase were comparable. All LEDGF/p75 variants bound equally well to LEDGF/p75 interacting partners JPO2 and PogZ. In addition, HIV-1 replication was evaluated in human somatic LEDGF/p75-knockout cells and LEDGF/p75-knockdown cells complemented with either wild-type LEDGF/p75 or the respective LEDGF/p75 variants. All variants rescued HIV-1 replication to wild-type levels, whereas LEDGF/p75 D366N, defective for interaction with HIV-1 integrase, did not. Although identified in a cohort of long-term nonprogressors, our study did not indicate that the I436S or T473I mutation in LEDGF/p75 affects the interaction with HIV-1 integrase.