Creative and Novel Ideas in HIV Research (CNIHR) Program

We will study the role of integration site distribution on the establishment of a latent reservoir and ultimately aim at preventing the establishment of a latent reservoir for HIV by manipulation of the HIV-1 integrase - LEDGF/p75 interaction. Our concept is based on the retargeting of HIV integration towards regions of the human genome that are less, or even not prone to reactivation. When successful, our strategy may lead to functional eradication of HIV. In 2002, our research group identified LEDGF/p75 (Lens Epithelium-Derived Growth Factor) as a novel cellular binding partner of HIV integrase. We and other validated LEDGF/p75 as a crucial cofactor of HIV integration and replication, targeting HIV integration into transcriptionally active regions. Overexpression of the integrase binding domain of LEDGF/p75 inhibited HIV replication in cultured cells (De Rijck et al. J Virol 2006; Llano et al. Science 2006) and we demonstrated protection of primary human CD4+ T cells against HIV infection as a proof-of-pinciple for antiviral therapy based on LEDGF/p75 (Vets et al. Mol Ther 2012). By engineering artificial LEDGF-chimeras, where we replaced the natural chromatin binding domain of LEDGF/p75 with CBX1, we were able to retarget HIV integration away from genes and into regions that are generally disfavored for integration, such as pericentric and silenced heterochromatin (Gijsbers et al. Mol Ther 2010). In addition, our group reported recently on the development of specific inhibitors of the LEDGF/p75 - HIV IN interaction, dubbed LEDGINs, that block HIV integration and replication at submicromolar concentrations (Christ et al. Nat Chem Biol 2010). These first-in-class small molecule inhibitors, together with the chimera to retarget HIV integration in the genome, provide us with the necessary tools to study the role of integration site distribution on the establishment of a latent reservoir. Here, we will study whether retargeting of integration affects the potential of HIV to recover from latency in simple cell models. We will determine whether interference with the LEDGF-IN interaction affects i) integration selection and ii) sensitivity of individual HIV clones to reactivation.