Screening of epigenetic modifiers identifies novel host-directed agents that suppress HIV-1 replication in primary human macrophages

Epigenetic modifications play a critical role in diverse biological processes, including HIV-1 replication in lymphoid and myeloid cells, particularly in the establishment and maintenance of latency. As such, epigenetic targets represent potential candidates for novel host directed therapy (HDT). In this study, we developed a novel in vitro screening platform using human primary macrophages, including both monocyte-derived macrophages and alveolar macrophages, infected with a replication-competent luminescent virus. In contrast to previous screens, this platform enables the identification of compounds and epigenetic targets that modulate viral replication during a spreading infection, capturing not only transcriptional regulation but other vulnerabilities across the complete HIV-1 life cycle. Our data reveal multiple novel compounds targeting distinct epigenetic regulators, effectively inhibiting viral replication at various stages in primary macrophages, which may serve as potential candidates/targets for HDT.