Identification of a novel small molecule facilitating HIV elimination by the "Shock-and-Kill" approach

Abstract

The development of antiretroviral therapy (ART) has significantly improved the prognosis of people living with HIV (PLWH). However, reservoirs of latent viruses represent a major barrier to achieving a complete cure of HIV infection. To overcome the burden of viral latency, the "Shock-and-Kill" strategy employs latency-reversing agents (LRAs) to reactivate the virus and thus render it susceptible to elimination. Existing LRAs are not optimal and there is an unmet need for improvement. By screening a small molecule library, we identified the novel LRA candidate 2-HSB (2-hydrido-2,2-spirobi(1,3,2-benzodioxaphosphole)) which not only reactivates latent HIV provirus but also induces specific cytopathic effects in both monocytic and T lymphocytic latent HIV reservoirs. Thus, this novel compound represents a dual "shock and kill" agent, unlike known LRAs which are limited to the "shock". The probable involvement of HIV-1 tat protein may account for its selectivity. Although both shock and kill effects seemed to be regulated by spleen tyrosine kinase, they were independent of each other, indicating that neither activation-induced cell death nor cell death-induced reactivation was occurring. Crucially, 2-HSB induced viral transcription in ART-suppressed PLWH samples in vitro. Our findings present 2-HSB as a promising dual-action compound for the "Shock and Kill" strategy, demonstrating efficacy in both transformed cell lines and clinically-relevant primary samples. These results raise the possibility of distinguishing the mode of action of the two effects, potentially leading to the development of a single agent causing both HIV-1 reactivation and elimination and contributing to the improvement of treatment.