(A) Domain structure of HIV-1 integrase (IN) and lens epithelium–derived growth factor (LEDGF/p75). HIV-1 IN consists of an N–terminal domain (NTD), a catalytic core domain (CCD) and a C–terminal domain (CTD) [3]. LEDGF/p75 consists of an integrase–binding domain (IBD), binding the viral IN, and a PWWP domain, binding epigenetic marks in the genome associated with active transcription such as H3K36me2/3 [38,39,40,41,42]. (B) LEDGF/p75 tethers HIV-1 IN to chromatin. LEDGF/p75 simultaneously binds HIV-1 IN with its integrase–binding domain (IBD) and chromatin through its PWWP domain, tethering HIV-1 IN to decondensed chromatin regions, tagged by H3K36me2/3 [38,39,40,41,42]. HIV-1 integration can be targeted away from H3K36me2/3 with the use of LEDGINs, small molecules that inhibit the interaction between HIV-1 IN and LEDGF/p75 [22,23]. (Figure created with Biorender.com on 17 December 2022).