Development of an Attenuated Tat Protein as a Highly-effective Agent to Specifically Activate HIV-1 Latency |
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| Authors: | Guannan Geng Bingfeng Liu Cancan Chen Kang Wu Jun Liu Yijun Zhang Ting Pan Jun Li Yue Yin Junsong Zhang Feng Huang Fei Yu Jingliang Chen Xiancai Ma Jie Zhou Ersheng Kuang Chao Liu Weiping Cai Hui Zhang |
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| Institution: | 1Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China;2Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China;3Department of Infectious Diseases, Guangzhou 8th People''s Hospital, Guangzhou, China |
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| Abstract: | Although combined antiretroviral therapy (cART) successfully decreases plasma viremia to undetectable levels, the complete eradication of human immunodeficiency virus type 1 (HIV-1) remains impractical because of the existence of a viral reservoir, mainly in resting memory CD4+ T cells. Various cytokines, protein kinase C activators, and histone deacetylase inhibitors (HDACi) have been used as latency-reversing agents (LRAs), but their unacceptable side effects or low efficiencies limit their clinical use. Here, by a mutation accumulation strategy, we generated an attenuated HIV-1 Tat protein named Tat-R5M4, which has significantly reduced cytotoxicity and immunogenicity, yet retaining potent transactivation and membrane-penetration activity. Combined with HDACi, Tat-R5M4 activates highly genetically diverse and replication-competent viruses from resting CD4+ T lymphocytes isolated from HIV-1-infected individuals receiving suppressive cART. Thus, Tat-R5M4 has promising potential as a safe, efficient, and specific LRA in HIV-1 treatment. |
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