Flying in the face of resistance: antiviral-independent benefit of HIV protease inhibitors on T-cell survival.
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.
Vlahakis
S R
SR
Division of Infectious Diseases, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. vlahakis.stacey@mayo.edu
Bren
G D
GD
Algeciras-Schimnich
A
A
Trushin
S A
SA
Schnepple
D J
DJ
Badley
A D
AD
D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D024882:Drug Resistance, Viral; D053222:Fas Ligand Protein / Q000037:antagonists & inhibitors / Q000633:toxicity; D005434:Flow Cytometry; D015696:Gene Products, tat / Q000037:antagonists & inhibitors / Q000633:toxicity; D016336:Gene Products, vpr / Q000037:antagonists & inhibitors / Q000633:toxicity; D015699:HIV Envelope Protein gp120 / Q000633:toxicity; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D019888:Nelfinavir / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors / Q000633:toxicity; D014779:Virus Replication / Q000187:drug effects; D054322:tat Gene Products, Human Immunodeficiency Virus; D054325:vpr Gene Products, Human Immunodeficiency Virus
D053222:Fas Ligand Protein; D015696:Gene Products, tat; D016336:Gene Products, vpr; D015699:HIV Envelope Protein gp120; D017320:HIV Protease Inhibitors; D019718:Receptors, CXCR4; D053221:TNF-Related Apoptosis-Inducing Ligand; D054322:tat Gene Products, Human Immunodeficiency Virus; D054325:vpr Gene Products, Human Immunodeficiency Virus; D019888:Nelfinavir