Drug-loaded red blood cell-mediated clearance of HIV-1 macrophage reservoir by selective inhibition of STAT1 expression.
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-(beta-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.
Magnani
Mauro
M
Institute of Biochemistry G Fornaini University of Urbino, Via Saffi 2, 61029, Urbino, Italy. magnani@uniurb.it
Balestra
Emanuela
E
Fraternale
Alessandra
A
Aquaro
Stefano
S
Paiardini
Mirko
M
Cervasi
Barbara
B
Casabianca
Anna
A
Garaci
Enrico
E
Perno
Carlo-Federico
CF
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000821:virology; D000209:Acute-Phase Proteins / Q000037:antagonists & inhibitors; D000970:Antineoplastic Agents / Q000494:pharmacology; D023241:Antiretroviral Therapy, Highly Active; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004197:Disease Reservoirs; D004912:Erythrocytes / Q000502:physiology* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000302:isolation & purification / Q000502:physiology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000821:virology; D008264:Macrophages / Q000821:virology*; D011533:Proviruses / Q000187:drug effects; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology*; D019562:Viral Load; D014779:Virus Replication
D000209:Acute-Phase Proteins; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D014740:Vidarabine; C024352:fludarabine