In vivo activation of latent HIV with a synthetic bryostatin analog effects both latent cell "kick" and "kill" in strategy for virus eradication

PLoS Pathogens

Christina M. Ramirez¹  Brian A. Loy²  Paul A. Wender²  Adam J. Schrier²  Katherine E. Near²  Akira Shimizu²  Steven M. Ryckbosch²  Matthew D. Marsden³  Jerome A. Zack³  Xiaomeng Wu⁴  Danielle Murray⁵  Tae-Wook Chun⁵ 

[1] Department of Biostatistics, School of Public Health, University of California Los Angeles, Los Angeles, California, United States of America;Department of Chemistry and Department of Chemical and Systems Biology, Stanford University, Stanford, California, United States of America;Department of Medicine, Division of Hematology and Oncology, University of California Los Angeles, Los Angeles, California, United States of America;Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, California, United States of America;National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America

关键词: HIV;    T cells;    Mouse models;    Viral persistence;    latency;    Cell staining;    Flow cytometry;    Spleen;    Antiretroviral therapy;   

DOI  :  10.1371/journal.ppat.1006575

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The ability of HIV to establish a long-lived latent infection within resting CD4+ T cells leads to persistence and episodic resupply of the virus in patients treated with antiretroviral therapy (ART), thereby preventing eradication of the disease. Protein kinase C (PKC) modulators such as bryostatin 1 can activate these latently infected cells, potentially leading to their elimination by virus-mediated cytopathic effects, the host’s immune response and/or therapeutic strategies targeting cells actively expressing virus. While research in this area has focused heavily on naturally-occurring PKC modulators, their study has been hampered by their limited and variable availability, and equally significantly by sub-optimal activity and in vivo tolerability. Here we show that a designed, synthetically-accessible analog of bryostatin 1 is better-tolerated in vivo when compared with the naturally-occurring product and potently induces HIV expression from latency in humanized BLT mice, a proven and important model for studying HIV persistence and pathogenesis in vivo. Importantly, this induction of virus expression causes some of the newly HIV-expressing cells to die. Thus, designed, synthetically-accessible, tunable, and efficacious bryostatin analogs can mediate both a “kick” and “kill” response in latently-infected cells and exhibit improved tolerability, therefore showing unique promise as clinical adjuvants for HIV eradication.

【 授权许可】

CC BY