More than 50% of the latent reservoir are maintained through clonal expansion. While ART effectively blocks new rounds of infection, HIV-1 promoter remains intact, drives HIV-1 expression and aberrant cancer-related gene expression, and contributes to HIV-1 integration site-related clonal expansion. New therapeutic approaches targeting the clonal expansion of HIV-1-infected cells is required to reduce the size of the latent reservoir. We hypothesize that suppressing HIV-1 transcription can disrupt HIV-1-driven clonal expansion of the infected cells.
We first developed a dual-reporter cell line model and screened a library of 1,430 FDA-approved small molecule compounds to identify HIV-1-suppressing agents. Second, we examined the effect of candidate HIV-1-suppressing agents on HIV-1 transcription and HIV-1-driven aberrant host gene transcription at the integration site. Third, we examined cellular transcriptional landscape of cells treated with candidate HIV-1-suppressin agents to understand how these agents affect host cell environment. Fourth, to understand whether candidate HIV-1-suppressing agents can disrupt the proliferation dynamics of HIV-1-infected cells, we examined the frequency of HIV-1-infected cells from HIV-1-infected individuals upon ex vivo T cell activation with and without ex vivo treatment of candidate HIV-1-suppressing agents.
We identified four FDA-approved drugs – JAK1 inhibitor filgotinib, JAK1/2 inhibitor ruxolitinib, spironolactone and guanine synthesis inhibitor mycophenolic acid – which reduce HIV-1-GFP reporter expression in cell line models and HIV-1 RNA transcription in CD4+ T cells from HIV-1-infected individuals. Among them, filgotinib, spironolactone and mycophenolic acid suppress HIV-1-driven aberrant host gene transcription and aberrant oncogenic protein production in a HIV-1-reporter cell line model. Filgotinib alters host transcriptional landscape by changing host RNA processing involving intron retention and RNA splicing. During CD3/CD28 induced T cell activation and proliferation, filgotinib reduces the frequency of cells harboring inducible HIV-1 ex vivo.
Filgotinib preferentially reduce the proliferation of HIV-1-infected cells upon T cell activation. HIV-1 suppressing agents serve as a new therapeutic approach to target the clonally expanding HIV-1-infected cells.