Identification of a Novel Small Molecule Facilitating HIV Elimination by the “Shock‐And‐Kill” Approach
ABSTRACT Antiretroviral therapy (ART) has markedly improved the prognosis of people living with HIV (PLWH); however, latent viral reservoirs remain a major barrier to a cure. The “Shock and Kill” strategy aims to reactivate latent provirus with latency‐reversing agents (LRAs) and subsequently eliminate the infected cells, yet most LRAs characterized to date provide only the “shock” component. Through screening a small‐molecule library, we identified 2‐hydrido‐2,2'‐spirobi(1,3,2‐benzodioxaphosphole) (2‐HSB) as a novel candidate that both reactivates latent HIV provirus and selectively induces cytopathic effects in latently infected reservoir cell lines, thereby exhibiting a dual “Shock and Kill” activity within a single compound. Mechanistically, the HIV‐1 tat protein appears to contribute to this selectivity. At the single‐cell level, the two effects appeared largely independent, indicating that, under the conditions tested, reactivation was not a consequence of cell death and vice versa. Importantly, 2‐HSB induced viral transcription in ex vivo CD4+ T cells from ART‐suppressed PLWH. Together, these findings identify 2‐HSB as a dual‐action candidate that reactivates latent HIV‐1 and preferentially induces cytopathic effects in reservoir cell‐line models, while supporting further mechanistic and ex vivo validation in primary reservoir‐bearing cells.