Inhibition of HIV-1 production and selective degradation of viral RNA by an amphibian ribonuclease.
Ribonucleases appear to have physiologic roles in host defense against cancer, viruses, and other parasites. Previously it was shown that select ribonucleases added to cells concurrently with virions blocked human immunodeficiency virus, type I (HIV-1) infection of H9 cells. We now report that a ribonuclease homologous to RNase A, named onconase, inhibits virus replication in chronically HIV-1-infected human cells without killing the virally infected cell. Examining the mechanism of this inhibition shows that onconase enters the infected cells and degrades HIV-1 RNA without degrading ribosomal RNA or the three different cellular messenger RNAs analyzed. The homologous human pancreatic RNase lacks anti-viral activity. Comparing recombinant forms of onconase and a onconase-human RNase chimera shows that the N-terminal 9 amino acids and the pyroglutamyl residue of onconase are required for full anti-viral activity. Thus extracellular ribonucleases can enter cells, metabolize select RNAs, and inhibit HIV virion production within viable replicating cells.
Saxena
S K
SK
Biochemistry Section of the Surgical Neurology Branch, NINDS, National Institutes of Health, Bethesda, Maryland 20892, USA.
Gravell
M
M
Wu
Y N
YN
Mikulski
S M
SM
Shogen
K
K
Ardelt
W
W
Youle
R J
RJ
D000998:Antiviral Agents; D004527:Egg Proteins / Q000378:metabolism* / Q000494:pharmacology; D005110:Extracellular Space / Q000201:enzymology; D016655:HIV Core Protein p24 / Q000032:analysis; D015497:HIV-1 / Q000254:growth & development*; D006801:Humans; D012333:RNA, Messenger / Q000378:metabolism; D012335:RNA, Ribosomal / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism*; D011994:Recombinant Proteins; D012260:Ribonucleases / Q000378:metabolism* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D004527:Egg Proteins; D016655:HIV Core Protein p24; D012333:RNA, Messenger; D012335:RNA, Ribosomal; D012367:RNA, Viral; D011994:Recombinant Proteins; D012260:Ribonucleases; C058703:ranpirnase