title: Administration of fludarabine-loaded autologous red blood cells in simian immunodeficiency virus-infected sooty mangabeys depletes pSTAT-1-expressing macrophages and delays the rebound of viremia after suspension of antiretroviral therapy.
abstract: A major limitation of highly active antiretroviral therapy is that it fails to eradicate human immunodeficiency virus (HIV) infection due to its limited effects on viral reservoirs carrying replication-competent HIV, including monocytes/macrophages (M/M). Therefore, therapeutic approaches aimed at targeting HIV-infected M/M may prove useful in the clinical management of HIV-infected patients. In previous studies, we have shown that administration of fludarabine-loaded red blood cells (RBC) in vitro selectively induces cell death in HIV-infected M/M via a pSTAT1-dependent pathway. To determine the in vivo efficacy of this novel therapeutic strategy, we treated six naturally simian immunodeficiency virus (SIV)-infected sooty mangabeys (SMs) with either 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA) only, fludarabine-loaded RBC only, or PMPA in association with fludarabine-loaded RBC. The rationale of this treatment was to target infected M/M with fludarabine-loaded RBC at a time when PMPA is suppressing viral replication taking place in activated CD4+ T cells. In vivo administration of fludarabine-loaded RBC was well tolerated and did not induce any discernible side effect. Importantly, addition of fludarabine-loaded RBC to PMPA delayed the rebound of viral replication after suspension of therapy, thus suggesting a reduction in the size of SIV reservoirs. While administrations of fludarabine-loaded RBC did not induce any change in the CD4+ or CD8+ T-cell compartments, we observed, in chronically SIV-infected SMs, a selective depletion of M/M expressing pSTAT1. This study suggests that therapeutic strategies based on the administration of fludarabine-loaded RBC may be further explored as interventions aimed at reducing the size of the M/M reservoirs during chronic HIV infection.
authors.affiliation: Institute of Biochemistry, University of Urbino, Urbino, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Cervasi
authors.forename: M
authors.initials: M
authors.lastname: Paiardini
authors.forename: S
authors.initials: S
authors.lastname: Serafini
authors.forename: A
authors.initials: A
authors.lastname: Fraternale
authors.forename: M
authors.initials: M
authors.lastname: Menotta
authors.forename: J
authors.initials: J
authors.lastname: Engram
authors.forename: B
authors.initials: B
authors.lastname: Lawson
authors.forename: S I
authors.initials: SI
authors.lastname: Staprans
authors.forename: G
authors.initials: G
authors.lastname: Piedimonte
authors.forename: C F
authors.initials: CF
authors.lastname: Perno
authors.forename: G
authors.initials: G
authors.lastname: Silvestri
authors.forename: M
authors.initials: M
authors.lastname: Magnani
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000818:Animals; D023241:Antiretroviral Therapy, Highly Active; D000998:Antiviral Agents / Q000008:administration & dosage; D016665:Cercocebus atys; D004337:Drug Carriers; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000821:virology*; D008297:Male; D019653:Myeloablative Agonists / Q000008:administration & dosage; D063065:Organophosphonates / Q000008:administration & dosage; D050794:STAT1 Transcription Factor / Q000378:metabolism; D016097:Simian Acquired Immunodeficiency Syndrome / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D016176:T-Lymphocyte Subsets / Q000187:drug effects; D000068698:Tenofovir; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D014766:Viremia / Q000188:drug therapy / Q000517:prevention & control / Q000821:virology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D004337:Drug Carriers; D019653:Myeloablative Agonists; D063065:Organophosphonates; D050794:STAT1 Transcription Factor; D000068698:Tenofovir; D014740:Vidarabine; D000225:Adenine; C024352:fludarabine