TY - JOUR
T1 - The Effect of Chloroquine on Immune Activation and Interferon Signatures Associated with HIV-1
AU - Jacobson, Jeffrey M.
AU - Bosinger, Steven E.
AU - Kang, Minhee
AU - Belaunzaran-Zamudio, Pablo
AU - Matining, Roy M.
AU - Wilson, Cara C.
AU - Flexner, Charles
AU - Clagett, Brian
AU - Plants, Jill
AU - Read, Sarah
AU - Purdue, Lynette
AU - Myers, Laurie
AU - Boone, Linda
AU - Tebas, Pablo
AU - Kumar, Princy
AU - Clifford, David
AU - Douek, Daniel
AU - Silvestri, Guido
AU - Landay, Alan L.
AU - Lederman, Michael M.
N1 - Funding Information:
We are indebted to Pamela Fried for editorial assistance, the clinicians who referred patients to the study, and patients who participated. Thisworkwas supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (Award Numbers UM1 AI068634, AI068636, AI76174, AI36219, and UM1 AI106701). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. AIDS Clinical Trial Group Site Grant Numbers: Case CRS (Site 2501) Grant UM1 AI069501; MetroHealth CRS (Site 2503) Grant UM1 AI 6950742; Penn Therapeutics CRS (Site 6201) Grant UM1 AI069534-09; Georgetown University CRS (Site 1008) Grant UM1 AI069494, CFAR P30-AI045008-17; Washington University in St. Louis CRS (Site 2101) Grant U01 AI69439; Johns Hopkins University CRS (Site 0201) Grant 2UM1 AI069465, UL1TR001079, Institute for Clinical and Translational Research; University of Pittsburgh CRS (Site 1001) Grant UM1AI069494; Vanderbilt University CRS (Site 3652) Grant AI069439, TR000445; University of Colorado CRS (Site 6101) Grant AI069432, UL1 TR001082; Chapel Hill CRS (Site 3201) Grants UM1 AI069423, CTSA: UL1TR001111, CFAR: P30 AI050410; Alabama CRS (Site 31788) Grant 5UM1AI069452-10; UC San Diego CRS (Site 701) Grant AI069432;Weill Cornell-Chelsea CRS (Site 7804) GrantUM1AI069419,UL1TR000457;Massachusetts General Hospital CRS (Site 101) Grant 2UM1AI069412-08; University of Cincinnati CRS (Site 2401) Grant UM1AI068636. We would also like to acknowledge the following additional investigators at participating sites: Case CRS: Kristen Allen, RN and Jane Baum RN; MetroHealth: Kim Whitely, RN and Traci Davis, RN; CRS-Penn Therapeutics: Wayne Wagner, RN; GeorgetownUniversity CRS: JosephG Timpone, Jr,MD; Washington University in St Louis CRS: Michael Klebert, PhD and Michael Royal, RPh; Johns Hopkins University CRS: Ilene Wiggins, RN and Andrea Weiss, BPharm; University of Pittsburgh CRS: Deborah McMahon, MD and Renee Weinman, BS CCRP; Vanderbilt University CRS:Marcia Free, RN and Michael Morgan, RN, FNP; University of Colorado CRS: M Graham Ray, RN and Thomas B Campbell, MD; Chapel Hill CRS: Jonathan Oakes, BA and Susan Blevins, MS ANP; Alabama CRS: Elizabeth Lindsey, RN and Kamellia Safavy, MSc; UC San Diego CRS: Kathleen Nuffer, NP and Dee Dee Pacheco; Weill Cornell-Chelsea CRS: Valery Hughes, NP and Todd Stroberg, RN; Massachusetts General Hospital CRS: Teri Flynn, ANP-BC and Amy Sbrolla, RN BSN; University of Cincinnati CRS: Eva Whitehead, RN, BSN and Carl J. Fichtenbaum, MD
Publisher Copyright:
© Copyright 2016, Mary Ann Liebert, Inc. 2016.
PY - 2016/7/1
Y1 - 2016/7/1
N2 - Immune activation associated with HIV-1 infection contributes to morbidity and mortality. We studied whether chloroquine, through Toll-like receptor (TLR) antagonist properties, could reduce immune activation thought to be driven by TLR ligands, such as gut-derived bacterial elements and HIV-1 RNAs. AIDS Clinical Trials Group A5258 was a randomized, double-blind, placebo-controlled study in 33 HIV-1-infected participants off antiretroviral therapy (ART) and 37 participants on ART. Study participants in each cohort were randomized 1:1 to receive chloroquine 250 mg orally for the first 12 weeks then cross over to placebo for 12 weeks or placebo first and then chloroquine. Combining the periods of chloroquine use in both arms of the on-ART cohort yielded a modest reduction in the proportions of CD8 T cells co-expressing CD38 and DR (median decrease = 3.0%, p = .003). The effect on immune activation in the off-ART cohort was likely confounded by increased plasma HIV-1 RNA during chloroquine administration (median 0.29 log10 increase, p < .001). Transcriptional analyses in the off-ART cohort showed decreased expression of interferon-stimulated genes in 5 of 10 chloroquine-treated participants and modest decreases in CD38 and CCR5 RNAs in all chloroquine-treated participants. Chloroquine modestly reduced immune activation in ART-treated HIV-infected participants. Clinical Trials Registry Number: NCT00819390.
AB - Immune activation associated with HIV-1 infection contributes to morbidity and mortality. We studied whether chloroquine, through Toll-like receptor (TLR) antagonist properties, could reduce immune activation thought to be driven by TLR ligands, such as gut-derived bacterial elements and HIV-1 RNAs. AIDS Clinical Trials Group A5258 was a randomized, double-blind, placebo-controlled study in 33 HIV-1-infected participants off antiretroviral therapy (ART) and 37 participants on ART. Study participants in each cohort were randomized 1:1 to receive chloroquine 250 mg orally for the first 12 weeks then cross over to placebo for 12 weeks or placebo first and then chloroquine. Combining the periods of chloroquine use in both arms of the on-ART cohort yielded a modest reduction in the proportions of CD8 T cells co-expressing CD38 and DR (median decrease = 3.0%, p = .003). The effect on immune activation in the off-ART cohort was likely confounded by increased plasma HIV-1 RNA during chloroquine administration (median 0.29 log10 increase, p < .001). Transcriptional analyses in the off-ART cohort showed decreased expression of interferon-stimulated genes in 5 of 10 chloroquine-treated participants and modest decreases in CD38 and CCR5 RNAs in all chloroquine-treated participants. Chloroquine modestly reduced immune activation in ART-treated HIV-infected participants. Clinical Trials Registry Number: NCT00819390.
UR - http://www.scopus.com/inward/record.url?scp=84976485600&partnerID=8YFLogxK
U2 - 10.1089/aid.2015.0336
DO - 10.1089/aid.2015.0336
M3 - Article
C2 - 26935044
AN - SCOPUS:84976485600
SN - 0889-2229
VL - 32
SP - 636
EP - 647
JO - AIDS Research and Human Retroviruses
JF - AIDS Research and Human Retroviruses
IS - 7
ER -