title: Antifibrotic therapy in simian immunodeficiency virus infection preserves CD4+ T-cell populations and improves immune reconstitution with antiretroviral therapy.
abstract: Even with prolonged antiretroviral therapy (ART), many human immunodeficiency virus-infected individuals have <500 CD4(+) T cells/µL, and CD4(+) T cells in lymphoid tissues remain severely depleted, due in part to fibrosis of the paracortical T-cell zone (TZ) that impairs homeostatic mechanisms required for T-cell survival. We therefore used antifibrotic therapy in simian immunodeficiency virus-infected rhesus macaques to determine whether decreased TZ fibrosis would improve reconstitution of peripheral and lymphoid CD4(+) T cells. Treatment with the antifibrotic drug pirfenidone preserved TZ architecture and was associated with significantly larger populations of CD4(+) T cells in peripheral blood and lymphoid tissues. Combining pirfenidone with an ART regimen was associated with greater preservation of CD4(+) T cells than ART alone and was also associated with higher pirfenidone concentrations. These data support a potential role for antifibrotic drug treatment as adjunctive therapy with ART to improve immune reconstitution.
authors.affiliation: Frederick National Laboratory, Leidos Biomedical Research.
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Estes
authors.affiliation: Department of Biostatistics, University of Minnesota, Minneapolis.
authors.forename: Cavan
authors.initials: C
authors.lastname: Reilly
authors.affiliation: Frederick National Laboratory, Leidos Biomedical Research.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Trubey
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center, Omaha.
authors.forename: Courtney V
authors.initials: CV
authors.lastname: Fletcher
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center, Omaha.
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Cory
authors.affiliation: Frederick National Laboratory, Leidos Biomedical Research.
authors.forename: Michael
authors.initials: M
authors.lastname: Piatak
authors.affiliation: Department of Medicine.
authors.forename: Samuel
authors.initials: S
authors.lastname: Russ
authors.affiliation: Department of Medicine.
authors.forename: Jodi
authors.initials: J
authors.lastname: Anderson
authors.affiliation: Department of Medicine.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Reimann
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, Maryland.
authors.forename: Robert
authors.initials: R
authors.lastname: Star
authors.affiliation: Department of Microbiology.
authors.forename: Anthony
authors.initials: A
authors.lastname: Smith
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Vermont, Burlington.
authors.forename: Russell P
authors.initials: RP
authors.lastname: Tracy
authors.affiliation: Department of Medicine.
authors.forename: Anna
authors.initials: A
authors.lastname: Berglund
authors.affiliation: Department of Medicine.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmidt
authors.affiliation: Frederick National Laboratory, Leidos Biomedical Research.
authors.forename: Vicky
authors.initials: V
authors.lastname: Coalter
authors.affiliation: Frederick National Laboratory, Leidos Biomedical Research.
authors.forename: Elena
authors.initials: E
authors.lastname: Chertova
authors.affiliation: Frederick National Laboratory, Leidos Biomedical Research.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Smedley
authors.affiliation: Department of Microbiology.
authors.forename: Ashley T
authors.initials: AT
authors.lastname: Haase
authors.affiliation: Frederick National Laboratory, Leidos Biomedical Research.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lifson
authors.affiliation: Department of Medicine.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Schacker
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D008198:Lymph Nodes / Q000473:pathology; D008253:Macaca mulatta; D011728:Pyridones / Q000627:therapeutic use*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D011728:Pyridones; C093844:pirfenidone
keywords: HIV; T-cell depletion; fibroblastic reticular cell network; fibrosis; immune reconstitution