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Published online before print August 21, 2003

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(Journal of Leukocyte Biology. 2003;74:764-771.)
© 2003 by Society for Leukocyte Biology

Drug-loaded red blood cell-mediated clearance of HIV-1 macrophage reservoir by selective inhibition of STAT1 expression

Mauro Magnani^*,1, Emanuela Balestra, Alessandra Fraternale^*, Stefano Aquaro, Mirko Paiardini^*, Barbara Cervasi^*, Anna Casabianca^*, Enrico Garaci and Carlo-Federico Perno^,

^* Institute of Biochemistry G. Fornaini, University of Urbino, Via Saffi 2, 61029, Urbino, Italy;
Dept. Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy and
INMI L. Spallanzani, Via Portuense 292, 00149 Rome, Italy

¹ Correspondence: Institute of Biological Chemistry "G. Fornaini", University of Urbino, Via Saffi 2, 61029, Urbino (PU) ITALY Email: magnani{at}uniurb.it

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-(ß-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.

Key Words: macrophages (M/M) • Fludarabine • erythrocytes (RBC)

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