title: Hydroxychloroquine drastically reduces immune activation in HIV-infected, antiretroviral therapy-treated immunologic nonresponders.
abstract: Despite optimal suppression of HIV replication, restoration of CD4(+) T cells is not always achieved in antiretroviral therapy-treated individuals. Defective CD4 recovery in immunologic nonresponders is possibly associated with TLR-mediated immune activation driven by alterations of gut permeability. Hydroxychloroquine (HCQ) reduces endosomal TLR signaling; thus, we verified whether HCQ could dampen immune activation and be associated with an increase in CD4(+) T cells. To this end, we enrolled in a prospective study 20 HIV-infected immunologic nonresponders (CD4 count < 200 cells/mL or CD4 increase < 5% in the last 12 months) who received 400 mg/day HCQ for 6 months. HCQ had a notable impact on immune activation as shown by significant modifications of the following parameters: (1) reduced plasma lipopolysaccharide; (2) decreased TLR4-expressing CD14(+) cells, TLR4-mediated signal transduction, and mRNA synthesis; (3) reduced percentages of activated CD4(+) (CD4(+)/Ki67(+)) and CD14(+) (CD14(+)/CD69(+)) cells; (4) increased T-regulatory cells (Tregs), naive Tregs, and TLR4-expressing Tregs; (5) augmented plasmacytoid dendritic cells and reduced IFNα-secreting plasmacytoid dendritic cells; and (6) reduced IL-6 and TNFα production. HCQ-induced immune modulation was associated with increased percentages of circulating CD4(+) T cells and was mostly retained 2 months after therapy interruption. HCQ reduces lipopolysaccharide/TLR-mediated immune activation; this compound could be a useful immunomodulant in HIV-infected patients. This study is registered at EutraCT as 2009-012499-28 with study number HLS01/2009-1-16-03-2009.
authors.affiliation: I Divisione Malattie Infettive, H.L. Sacco, Milan, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Piconi
authors.forename: Serena
authors.initials: S
authors.lastname: Parisotto
authors.forename: Giuliano
authors.initials: G
authors.lastname: Rizzardini
authors.forename: Simone
authors.initials: S
authors.lastname: Passerini
authors.forename: Roberta
authors.initials: R
authors.lastname: Terzi
authors.forename: Barbara
authors.initials: B
authors.lastname: Argenteri
authors.forename: Paola
authors.initials: P
authors.lastname: Meraviglia
authors.forename: Amedeo
authors.initials: A
authors.lastname: Capetti
authors.forename: Mara
authors.initials: M
authors.lastname: Biasin
authors.forename: Daria
authors.initials: D
authors.lastname: Trabattoni
authors.forename: Mario
authors.initials: M
authors.lastname: Clerici
mesh_terms: D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D015703:Antigens, CD / Q000032:analysis / Q000096:biosynthesis; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000821:virology; D016207:Cytokines / Q000032:analysis / Q000096:biosynthesis; D005260:Female; D005434:Flow Cytometry; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000254:growth & development; D006801:Humans; D006886:Hydroxychloroquine / Q000008:administration & dosage / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007155:Immunologic Factors / Q000008:administration & dosage / Q000627:therapeutic use*; D019394:Ki-67 Antigen / Q000032:analysis / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000821:virology; D011446:Prospective Studies; D015398:Signal Transduction / Q000187:drug effects; D051193:Toll-Like Receptors / Q000032:analysis* / Q000096:biosynthesis; D019562:Viral Load / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D015703:Antigens, CD; D016207:Cytokines; D007155:Immunologic Factors; D019394:Ki-67 Antigen; D051193:Toll-Like Receptors; D006886:Hydroxychloroquine