HIV-1 can integrate viral DNA into host cell chromosomes and establish a long-term stable latent viral reservoir, a major obstacle in curing HIV-1 infection. The reactivation of latent proviruses with latency-reversing agents (LRAs) is a prerequisite for the eradication of viral reservoirs. Previous reports have shown that tannic acid (TA) exerts several biological functions, including antioxidant and antitumor activities. Here, we identified a novel function of TA as a reactivator of HIV-1 latency. TA showed similar features to the HIV-1 transactivator of transcription (Tat) and was able to reactivate a larger number of proviruses from various integration sites. TA also showed a strong synergistic effect with other LRAs acting on different signaling pathways. Further studies revealed that the polycomb repressive complex 1 component, chromobox protein homolog 4 (CBX4), is specifically degraded by TA through ubiquitination. CBX4 is associated with the tri-methylation at lysine 27 of histone H3 (H3K27me3) which was enriched on HIV-1 long terminal repeat regions. The TA-induced CBX4 degradation decreased the H3K27me3 enrichment and subsequently enhanced the transcriptional activity of the integrated proviruses. These results suggest that TA is an efficient LRA aiming to a new target for HIV-1 latency, which could be developed to eradicate latent proviruses.IMPORTANCEHIV-1 remains a global health challenge, with its ability to integrate into the host genome and evade the effects of drugs. To overcome this obstacle, the "shock and kill" strategy was proposed, targeting the reactivation of latent HIV-1 for subsequent eradication through antiretroviral medication and immune system reinforcement. Here, we found a new reactivator for HIV-1 latency, tannic acid (TA), which can reactivate HIV-1 latency widely and deeply. Moreover, we demonstrated that TA could promote the interaction between the polycomb repressive complex 1 component CBX4 and the E3 ubiquitin ligase cullin 4A (CUL4A), resulting in CBX4 degradation through the ubiquitin-proteasome system. These events reduce H3K27me3 enrichment in the HIV-1 long terminal repeat region, thereby promoting HIV-1 transcription and ultimately reactivating HIV-1 latent infection. Our work may facilitate the identification of new latency-reversing agents and provide more theoretical evidence for the molecular mechanism of HIV-1 latency.
Keywords: CBX4; HIV-1 latent reservoir; reactivation; tannic acid (TA).