Targeted cytotoxic therapy kills persisting HIV infected cells during ART

• Published in: PLoS pathogens Vol. 10; no. 1; p. e1003872
• Main Authors: Denton, Paul W, Long, Julie M, Wietgrefe, Stephen W, Sykes, Craig, Spagnuolo, Rae Ann, Snyder, Olivia D, Perkey, Katherine, Archin, Nancie M, Choudhary, Shailesh K, Yang, Kuo, Hudgens, Michael G, Pastan, Ira, Haase, Ashley T, Kashuba, Angela D, Berger, Edward A, Margolis, David M, Garcia, J Victor
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.01.2014; Public Library of Science (PLoS)
• Subjects: Acquired immune deficiency syndrome; AIDS; Animals; Anti-Retroviral Agents - immunology; Anti-Retroviral Agents - therapeutic use; Antiviral agents; Biology; Cell interaction; Dosage and administration; Drug therapy; HIV; HIV infection; HIV Infections - blood; HIV Infections - drug therapy; HIV Infections - immunology; HIV-1 - immunology; HIV-1 - metabolism; Human immunodeficiency virus; Humans; Immunotoxins - immunology; Immunotoxins - pharmacology; Kinases; Medical research; Medicine; Mice; Mice, Inbred NOD; Mice, SCID; Microbiological research; Prevention; RNA, Viral - blood; RNA, Viral - immunology; United States
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1003872

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.