“Small Molecules Effective for Disruption of HIV-1 Latency“, by Seyedeh Pargol Hashemi, PhD candidate in Sadowski Lab.
Tuesday, August 20, 2019 at 9:00 am, Room 203, Graduate Student Centre, 6371 Crescent Road.
Although antiretroviral therapies have improved the outlook of the HIV epidemic by controlling virus replication, they do not provide a cure. The major barrier to development of a cure lies in the virus’s ability to become transcriptionally silent as chromosomally integrated provirus. The presence of latently infected cells that harbor transcriptionally repressed viral genomes, predominately consisting of long-lived memory CD4+ T cells, gives rise to cellular reservoirs that are impenetrable by current therapies. Therefore, devising ways to selectively target these latent reservoirs is imperative for the long-term management of the disease. My thesis focuses on the shock phase of a proposed cure strategy known as “shock and kill,” which aims to induce latent HIV-1 reservoirs that could then be purged via a boosted immune response, specific targeting of infected cells, or by viral-induced apoptosis. To this end, I identified five novel small molecule compounds, of a class commonly referred to as latency reversing agents (LRAs), that are capable of reversing HIV latency without affecting the general T cell activation state. These compounds exhibit synergy for reactivation of latent provirus with other LRAs, in particular, ingenol-3-angelate. One compound, designated PH02, was efficient at reactivating viral transcription in several cell lines bearing HIV-1 reporters at different integration sites. Furthermore, this compound was capable of reversing latency in resting CD4+ T lymphocytes from patients on antiretroviral therapy, while producing minimal cellular toxicity. The combination of PH02 and ingenol-3-angelate produces a strong synergistic effect of reactivation, as demonstrated by a quantitative viral outgrowth assay on CD4+ T lymphocytes from HIV-1-infected individuals. A comparison of similar efforts from other groups is provided, with the goal of illustrating the diversity of molecular scaffolds that can produce HIV-1 latency reversing activity. I expect these results will contribute to a deeper understanding of mechanisms regulating HIV-1 latency but also will provide insight towards design of optimized structures for development of highly effective LRAs capable of forcing a purge of the persistent HIV-1 infection.