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Drug‐loaded red blood cell‐mediated clearance of HIV‐1 macrophage reservoir by selective inhibition of STAT1 expression
Author(s) -
Magnani Mauro,
Balestra Emanuela,
Fraternale Alessandra,
Aquaro Stefano,
Paiardini Mirko,
Cervasi Barbara,
Casabianca Anna,
Garaci Enrico,
Perno CarloFederico
Publication year - 2003
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0403156
Subject(s) - biology , fludarabine , macrophage , in vivo , immunology , drug , virology , vidarabine , pharmacology , in vitro , chemotherapy , biochemistry , genetics , microbiology and biotechnology , cyclophosphamide
Current highly active antiretroviral therapy (HAART) cannot eliminate HIV‐1 from infected persons, mainly because of the existence of refractory viral reservoir(s). Beyond latently‐infected CD4+‐T lymphocytes, macrophages (M/M) are important persistent reservoirs for HIV in vivo, that represent a major obstacle to HIV‐1 eradication. Therefore, a rational therapeutic approach directed to the selective elimination of long‐living HIV‐infected M/M may be relevant in the therapy of HIV infection. Here we report that HIV‐1 chronic infection of human macrophages results in the marked increase of expression and phosphorylation of STAT1, a protein involved in the regulation of many functions such as cell growth, differentiation, and maintenance of cellular homeostasis, thereby providing a new molecular target for drug development. A single and brief exposure to 9‐(β‐D‐arabinofuranosyl)‐2‐fluoroadenine 5′‐monophosphate (FaraAMP, Fludarabine), a potent antileukemic nucleoside analog active against STAT1 expressing cells, selectively kills macrophage cultures infected by HIV‐1 without affecting uninfected macrophages. Furthermore, encapsulation of Fludarabine into autologous erythrocytes (RBC) and targeting to macrophages through a single‐18 h treatment with drug‐loaded RBC, not only abolishes the Fludarabine‐mediated toxic effect on non‐phagocytic cells, but also enhances the selective killing of HIV‐infected macrophages. As a final result, a potent (>98%) and long‐lasting (at least 4 weeks without rebound) inhibition of virus release from drug‐loaded RBC‐treated chronically‐infected macrophages was achieved. Taken together, the evidence of HIV‐1‐induced increase of STAT1, and the availability of a selective drug targeting system, may prove useful in the design of new pharmacological treatments to clear the HIV‐1 macrophage reservoir.