RNase L inhibitor is induced during human immunodeficiency virus type 1 infection and down regulates the 2-5A/RNase L pathway in human T cells.
The interferon-regulated 2-5A/RNase L pathway plays a major role in the antiviral and antiproliferative activities of these cytokines. Several viruses, however, have evolved strategies to escape the antiviral activity of the 2-5A/RNase L pathway. In this context, we have cloned a cDNA coding for the RNase L inhibitor (RLI), a protein that specifically inhibits RNase L and whose regulated expression in picornavirus-infected cells down regulates the activity of the 2-5A/RNase L pathway. We show here that RLI increases during the course of human immunodeficiency virus type 1 (HIV-1) infection, which may be related to the downregulation of RNase L activity that has been described to occur in HIV-infected cells. In order to establish a possible causal relationship between these observations, we have stably transfected H9 cells with RLI sense or antisense cDNA-expressing vectors. The overexpression of RLI causes a decrease in RNase L activity and a twofold enhancement of HIV production. This increase in HIV replication correlates with an increase in HIV RNA and proteins. In contrast, reduction of RLI levels in RLI antisense cDNA-expressing clones reverses the inhibition of RNase L activity associated with HIV multiplication and leads to a threefold decrease in the viral load. This anti-HIV activity correlated with a decrease in HIV RNA and proteins. These findings demonstrate that the level of RLI, via its modulation of RNase L activity, can severely impair HIV replication and suggest the involvement of RLI in the inhibition of the 2-5A/RNase L system observed during HIV infection.
Martinand
C
C
Institut de Génétique Moléculaire de Montpellier (UMR 5535, CNRS-Université de Montpellier II), 34293 Montpellier Cedex 5, France.
Montavon
C
C
Salehzada
T
T
Silhol
M
M
Lebleu
B
B
Bisbal
C
C
D000163:Acquired Immunodeficiency Syndrome / Q000378:metabolism*; D000227:Adenine Nucleotides / Q000037:antagonists & inhibitors*; D002460:Cell Line; D015536:Down-Regulation; D004722:Endoribonucleases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D009843:Oligoribonucleotides / Q000037:antagonists & inhibitors*; D014162:Transfection; D014779:Virus Replication
D000227:Adenine Nucleotides; D004791:Enzyme Inhibitors; D009843:Oligoribonucleotides; C023505:2',5'-oligoadenylate; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease