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Flying in the Face of Resistance: Antiviral‐independent Benefit of HIV Protease Inhibitors on T‐cell Survival
Author(s) -
Vlahakis S R,
Bren G D,
AlgecirasSchimnich A,
Trushin S A,
Schnepple D J,
Badley A D
Publication year - 2007
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/sj.clpt.6100140
Subject(s) - apoptosis , programmed cell death , protease , human immunodeficiency virus (hiv) , viral replication , virology , biology , tumor necrosis factor alpha , virus , immunology , cancer research , medicine , enzyme , biochemistry
Human immunodeficiency virus (HIV) infection results in excessive apoptosis of infected and uninfected cells, mediated by host and viral factors present in plasma. As HIV protease inhibitors (PIs) have intrinsic antiapoptotic properties, we questioned whether HIV PIs could block HIV‐induced CD4+ T‐cell death independent of their effects on HIV replication. We demonstrate that HIV PIs block the death of CD4+ T cells induced by HIV glycoprotein 120 (gp120), Vpr, and Tat, as well as host signals Fas ligand, tumor necrosis factor, and tumor necrosis factor‐related apoptosis‐inducing ligand. Using gp120/CXCR4 as a model, we show that the HIV PIs specifically block mitochondrial apoptosis signaling. Furthermore, HIV PIs inhibit CD4+ T‐cell death induced by viruses with high‐level resistance to PIs ( P <0.01) and apoptosis induced by serum of HIV patients with known resistance to HIV PIs ( P =0.01). Together, these results show that HIV PIs block CD4+ T‐cell death and have a beneficial effect on CD4+ T‐cell survival despite PI resistance. Clinical Pharmacology & Therapeutics (2007) 82 , 294–299; doi: 10.1038/sj.clpt.6100140 ; published online 14 March 2007