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. Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Cervasi, B., Paiardini, M., Serafini, S., Fraternale, A., Menotta, M., Engram, J., et al. (2006). 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. JOURNAL OF VIROLOGY, 80(21), 10335-10345 [10.1128/JVI.00472-06].

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

PERNO, CARLO FEDERICO;
2006-01-01

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. Copyright © 2006, American Society for Microbiology. All Rights Reserved.
2006
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/07 - MICROBIOLOGIA E MICROBIOLOGIA CLINICA
English
Con Impact Factor ISI
CD4 antigen; CD8 antigen; fludarabine; STAT1 protein; tenofovir; absence of side effects; animal cell; animal experiment; animal model; animal tissue; antiviral activity; article; autotransplantation; CD4+ T lymphocyte; CD8+ T lymphocyte; cell compartmentalization; Cercocebus; chronic disease; controlled study; disease severity; drug efficacy; drug erythrocyte level; erythrocyte transfusion; female; highly active antiretroviral therapy; Human immunodeficiency virus infection; in vivo study; macrophage function; male; monocyte; nonhuman; priority journal; protein expression; rebound; Simian immunodeficiency virus; viremia; virus cell interaction; virus infection; virus replication; Adenine; Animals; Antiretroviral Therapy, Highly Active; Antiviral Agents; Cercocebus atys; Drug Carriers; Erythrocytes; Female; Humans; Macrophages; Male; Myeloablative Agonists; Phosphonic Acids; Simian Acquired Immunodeficiency Syndrome; STAT1 Transcription Factor; T-Lymphocyte Subsets; Vidarabine; Viremia; Virus Replication; Human immunodeficiency virus; Simian immunodeficiency virus
11
Cervasi, B., Paiardini, M., Serafini, S., Fraternale, A., Menotta, M., Engram, J., et al. (2006). 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. JOURNAL OF VIROLOGY, 80(21), 10335-10345 [10.1128/JVI.00472-06].
Cervasi, B; Paiardini, M; Serafini, S; Fraternale, A; Menotta, M; Engram, J; Lawson, B; Staprans, S; Piedimonte, G; Perno, Cf; Silvestri, G; Magnani, M
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/35451
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