D10 is the first Tat activator available and the first LRA that targets an HIV protein, and induces strong HIV production by latent cell lines and latent cells from people living with HIV-1.
Abstract
Despite its efficiency to prevent viral multiplication, antiretroviral therapy does not affect HIV-1 latently-infected cells. These cells do not produce significant amounts of viruses and constitute HIV-1 reservoir. To purge this long-lived viral reservoir, the "shock and kill" strategy relies on the use of latency reversing agents (LRAs) to induce activation of latent cells. All LRAs developed until now target cellular proteins and are therefore not specific for HIV-infected cells. Here we present a new LRA that binds and activates HIV-1 Tat which is the key regulator for viral transcription and latency reversal. This molecule termed D10 was designed to bind to the major groove of the Tat protein, and found to activate Tat transcriptional activity by stabilizing the HIV transcription complex. This LRA induces strong HIV production by latent cell lines and latent cells from people living with HIV-1. On latent cells from PBMCs, D10 is active at ∼50 nM, the concentration required to stabilize HIV transcription complex. D10 is the first Tat activator available and the first LRA that targets an HIV protein.
A simple and reproducible assay to identify compounds capable of reactivating latent virus, a key step in cure strategies, is developed and validated and identified Tandutinib, a tyrosine kinase and mTOR inhibitor, as a novel LRA candidate with appreciable latency-reversing activity in the ACH2 model.
A. Neri, Arianna Rotili, Elena Morrocchi et al.· Microbiology spectrum· 0 citations
Despite the highly potent antiretroviral therapies, HIV-1 establishes persistent infection and causes chronic inflammation in people living with HIV-1 (PLWH). Beyond CD4+ T cells, HIV-1 infects myeloid cells, including circulating monocytes and tissue-resident macrophages, and integrates with host genomes to form stable viral reservoirs. To achieve a functional HIV cure, latency-promoting agents (LPAs) have been developed for the "block-and-lock" strategy to reinforce deep HIV-1 latency and permanently silence proviruses. However, most LPAs have been tested mainly in CD4+ T cells, and their efficacy in myeloid cells remains unclear. In this study, we reported that levosimendan (LSM), a drug approved for clinic use to treat heart failures, is able to inhibit HIV lytic infection and reactivation in myeloid cells. LSM blocked viral lytic reactivation in HIV-1 latently infected monocytic cells (TH89GFP, U1) and microglial cells (HC69). LSM also inhibited HIV infection in human induced pluripotent stem cells (iPSCs) derived microglia (iMG), primary human resident liver macrophages (Kupffer cells) as well as human monocyte-derived macrophages (MDMs). Furthermore, we demonstrated that overexpression of a predicted drug target of LSM, the conserved serine/threonine kinase RIOK1 (RIO kinase 1), overcomes LSM's anti-HIV effect. Overall, our studies concluded that LSM is a promising LPA to inhibit HIV-1 infection in myeloid cells via counteracting RIOK1.
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