Sorafenib enforces HIV-1 latency by selectively inhibiting PKC-driven STAT1/3 serine 727 phosphorylation
4 affiliations
- 1Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- 2Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine of Sun Yat-sen University, Guangzhou, China
- 3Department of Immunology and Microbiology, Zhongshan School of Medicine of Sun Yat-sen University, Guangzhou, China
- 4National Engineering Technology Research Center for Combined Vaccines, Wuhan, China
Abstract
Eliminating the latent HIV-1 reservoir remains a major barrier to achieving a functional cure. The “block-and-lock” strategy aims to enforce durable transcriptional silencing of proviruses, thereby preventing viral rebound upon interruption of antiretroviral therapy. However, the molecular mechanisms governing stable latency remain incompletely understood. Here, we identify protein kinase C (PKC)-dependent phosphorylation of STAT1 and STAT3 at serine 727 as a previously unrecognized regulatory checkpoint controlling HIV-1 transcriptional reactivation. Pharmacological inhibition of this axis using sorafenib, a clinically approved multi-kinase inhibitor, robustly suppresses HIV-1 reactivation across multiple latency models and promotes the establishment of latency in primary CD4+ T cells. Mechanistically, sorafenib attenuates phorbol 12-myristate 13-acetate (PMA)-induced activation of the JAK-STAT and PI3K-Akt signaling pathways, and selectively blocks PKC-mediated phosphorylation of STAT1/3 at serine 727 without affecting canonical tyrosine phosphorylation (Y701/Y705). This selective inhibition disrupts transcriptional activation at the HIV-1 long terminal repeat (LTR), thereby preventing viral reactivation. Importantly, sorafenib does not induce detectable cytotoxicity or alter activation and exhaustion markers in primary CD4+ T cells, supporting a favorable safety profile in vitro. Collectively, our findings define a critical role for STAT1/3 Ser727 in the regulation of HIV-1 latency and establish sorafenib as a promising latency-promoting agent for future applications in the development of a functional cure for HIV-1.
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BibTeX
@article{wang2026sorafenib,
title = {{Sorafenib enforces HIV-1 latency by selectively inhibiting PKC-driven STAT1/3 serine 727 phosphorylation}},
author = {Peipei Wang and Zhuoyue Meng and Jiasheng Zhou and Huixin Wu and Wei Wang and Zhiliang Gao and Ying Zhang and Jinfeng Cai},
journal = {Antimicrobial Agents and Chemotherapy},
year = {2026},
month = aug,
doi = {10.1128/aac.00540-26},
url = {https://doi.org/10.1128/aac.00540-26},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Sorafenib enforces HIV-1 latency by selectively inhibiting PKC-driven STAT1/3 serine 727 phosphorylation
AU - Peipei Wang
AU - Zhuoyue Meng
AU - Jiasheng Zhou
AU - Huixin Wu
AU - Wei Wang
AU - Zhiliang Gao
AU - Ying Zhang
AU - Jinfeng Cai
PY - 2026
DA - 2026/08/03
JO - Antimicrobial Agents and Chemotherapy
DO - 10.1128/aac.00540-26
UR - https://doi.org/10.1128/aac.00540-26
AB - Eliminating the latent HIV-1 reservoir remains a major barrier to achieving a functional cure. The “block-and-lock” strategy aims to enforce durable transcriptional silencing of proviruses, thereby preventing viral rebound upon interruption of antiretroviral therapy. However, the molecular mechanisms governing stable latency remain incompletely understood. Here, we identify protein kinase C (PKC)-dependent phosphorylation of STAT1 and STAT3 at serine 727 as a previously unrecognized regulatory checkpoint controlling HIV-1 transcriptional reactivation. Pharmacological inhibition of this axis using sorafenib, a clinically approved multi-kinase inhibitor, robustly suppresses HIV-1 reactivation across multiple latency models and promotes the establishment of latency in primary CD4+ T cells. Mechanistically, sorafenib attenuates phorbol 12-myristate 13-acetate (PMA)-induced activation of the JAK-STAT and PI3K-Akt signaling pathways, and selectively blocks PKC-mediated phosphorylation of STAT1/3 at serine 727 without affecting canonical tyrosine phosphorylation (Y701/Y705). This selective inhibition disrupts transcriptional activation at the HIV-1 long terminal repeat (LTR), thereby preventing viral reactivation. Importantly, sorafenib does not induce detectable cytotoxicity or alter activation and exhaustion markers in primary CD4+ T cells, supporting a favorable safety profile in vitro. Collectively, our findings define a critical role for STAT1/3 Ser727 in the regulation of HIV-1 latency and establish sorafenib as a promising latency-promoting agent for future applications in the development of a functional cure for HIV-1.
SN - 0066-4804
SN - 1098-6596
ER -