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Small molecules effective for disruption of HIV-1 latency

University of British Columbia

Although antiretroviral therapies have improved the outlook of the HIV epidemic, 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, 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.  This 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. Accordingly, research over the past decade has resulted in identification of small molecules capable of inducing HIV-1 latent reservoirs, by reactivation of viral transcription. Molecules with this capability, known as latency-reversing agents (LRAs). Thus far, none of the LRAs examined in clinical trials have reduced the size of persistent HIV-1 infection. Therefore, new classes of LRAs must be identified. To this end, I identified five novel 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 in vitro 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. 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. 

Text

2019-10-01

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/71810

Biochemistry and Molecular Biology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/