Targeted Cytotoxic Therapy Kills Persisting HIV Infected Cells During ART

PLoS Pathogens

Michael G. Hudgens¹  Ashley T. Haase²  Katherine Perkey²  Stephen W. Wietgrefe²  Rae Ann Spagnuolo³  David M. Margolis³  Paul W. Denton³  Julie M. Long³  Shailesh K. Choudhary³  J. Victor Garcia³  Nancie M. Archin³  Olivia D. Snyder³  Angela D. Kashuba⁴  Kuo Yang⁴  Craig Sykes⁴  Ira Pastan⁵  Edward A. Berger⁶ 

[1] Department of Biostatistics, UNC Center for AIDS Research, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America;Department of Microbiology, University of Minnesota, Minneapolis, Minnesota, United States of America;Division of Infectious Diseases, Department of Medicine, UNC Center for AIDS Research, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America;Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, UNC Center for AIDS Research, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America;Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America;Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America

关键词: Antiretroviral therapy;    HIV;    HIV infections;    Blood plasma;    Mouse models;    Antiretrovirals;    Blood;    Viral persistence;    latency;   

DOI  :  10.1371/journal.ppat.1003872

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Antiretroviral therapy (ART) can reduce HIV levels in plasma to undetectable levels, but rather little is known about the effects of ART outside of the peripheral blood regarding persistent virus production in tissue reservoirs. Understanding the dynamics of ART-induced reductions in viral RNA (vRNA) levels throughout the body is important for the development of strategies to eradicate infectious HIV from patients. Essential to a successful eradication therapy is a component capable of killing persisting HIV infected cells during ART. Therefore, we determined the in vivo efficacy of a targeted cytotoxic therapy to kill infected cells that persist despite long-term ART. For this purpose, we first characterized the impact of ART on HIV RNA levels in multiple organs of bone marrow-liver-thymus (BLT) humanized mice and found that antiretroviral drug penetration and activity was sufficient to reduce, but not eliminate, HIV production in each tissue tested. For targeted cytotoxic killing of these persistent vRNA+ cells, we treated BLT mice undergoing ART with an HIV-specific immunotoxin. We found that compared to ART alone, this agent profoundly depleted productively infected cells systemically. These results offer proof-of-concept that targeted cytotoxic therapies can be effective components of HIV eradication strategies.

【 授权许可】

CC BY