title: Targeted cytotoxic therapy kills persisting HIV infected cells during ART.
abstract: 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.
authors.affiliation: 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.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Denton
authors.affiliation: 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.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Long
authors.affiliation: Department of Microbiology, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Wietgrefe
authors.affiliation: 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.
authors.forename: Craig
authors.initials: C
authors.lastname: Sykes
authors.affiliation: 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.
authors.forename: Rae Ann
authors.initials: RA
authors.lastname: Spagnuolo
authors.affiliation: 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.
authors.forename: Olivia D
authors.initials: OD
authors.lastname: Snyder
authors.affiliation: Department of Microbiology, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Katherine
authors.initials: K
authors.lastname: Perkey
authors.affiliation: 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.
authors.forename: Nancie M
authors.initials: NM
authors.lastname: Archin
authors.affiliation: 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.
authors.forename: Shailesh K
authors.initials: SK
authors.lastname: Choudhary
authors.affiliation: 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.
authors.forename: Kuo
authors.initials: K
authors.lastname: Yang
authors.affiliation: Department of Biostatistics, UNC Center for AIDS Research, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hudgens
authors.affiliation: Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Ira
authors.initials: I
authors.lastname: Pastan
authors.affiliation: Department of Microbiology, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Ashley T
authors.initials: AT
authors.lastname: Haase
authors.affiliation: 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.
authors.forename: Angela D
authors.initials: AD
authors.lastname: Kashuba
authors.affiliation: Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Berger
authors.affiliation: 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.
authors.forename: David M
authors.initials: DM
authors.lastname: Margolis
authors.affiliation: 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.
authors.forename: J Victor
authors.initials: JV
authors.lastname: Garcia
mesh_terms: D000818:Animals; D044966:Anti-Retroviral Agents / Q000276:immunology / Q000627:therapeutic use*; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D015497:HIV-1 / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D000922:Immunotoxins / Q000276:immunology / Q000494:pharmacology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D012367:RNA, Viral / Q000097:blood* / Q000276:immunology
chemical_list: D044966:Anti-Retroviral Agents; D000922:Immunotoxins; D012367:RNA, Viral