Maarten van de Klundert

There is no cure of HIV infection due to latent intact HIV in cellular reservoirs, mainly in resting CD4+ cells. Several latency reversing agents (LRA) have been identified but no reduction in the reservoirs has been achieved in vivo. We screened a CRISPR-CAS knockout library targeting 2.000 drugable human genes and identified several novel genes maintaining HIV latency including C-terminal Src kinase (CSK). When inhibiting CSK, reactivation of latent HIV was seen in vitro. We will now further investigate the therapeutic potential of novel LRAs using state-of-the-art model systems. Our plan includes i) CRISPR-CAS screening for more druggable targets that reverse latency in GKO reporter virus infected Jurkat and primary human T cells

ii) identification of novel LRAs aand testing of small molecule inhibitors, including the CSK inhibitor

iii) testing selected LRAs on primary CD4+ T-cells from patients with suppressive viremia, assessing the reactivation of the replication competent reservoir and iv) in a subset of patients correlate variations in the reactivation potential to the integration sites in eu- or heterochromatin of the proviral HIV DNA. Our novel assays and approaches in HIV latency research will facilitate the identification for novel efficient LRAs and open new pathways towards functional HIV cure.