Oligonucleotide-mediated retroviral RNase H activation leads to reduced HIV-1 titer in patient-derived plasma.
BACKGROUND
The retroviral RNase H is essential for viral replication. This component has not yet been extensively studied for antiviral therapy. It can be activated by an oligodeoxynucleotide (ODN) resulting in self-destruction of the virions.


OBJECTIVE
To examine antiviral potential of ODN in clinical samples using plasma of HIV-1-infected patients.


METHODS
Plasma of 19 HIV-1-infected patients from Zurich and 10 HIV-1 isolates from Africa and drug-resistant strains were processed for ex-vivo treatment.


METHODS
Cell-free virions were treated with ODN in the plasma and HIV RNA was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Furthermore, infectivity of the treated virions was tested on primary human peripheral blood mononuclear cells.


RESULTS
Cell-free virions in plasma contained significantly less intact HIV RNA upon treatment with ODN (P = 0.0004), and their infectivity was decreased 52-fold (P = 0.0004). In 39% of the Zurich samples, infectivity was reduced more than 10-fold, in 33% more than 100-fold, and in 28% more than 1000-fold. Also, the isolates from Africa exhibited a 63-fold reduction in infectivity (P = 0.0069) with 80% of the isolates responding more than 10-fold, 40% more than 100-fold, and 10% more than 1000-fold.


CONCLUSIONS
Significant reduction of plasma HIV RNA levels and infectivity of treated virions was achieved on the basis of induced self-destruction of HIV observed with clinical samples. Reduction of viral load ex vivo was designed as model for potential effects in vivo. Premature activation rather than inhibition of a viral enzyme could be a model strategy for future antiretroviral control.
Heinrich
Jochen
J
Institute of Medical Virology, University of Zurich, Zurich, Switzerland.
Mathur
Srikanth
S
Matskevich
Alexey A
AA
Moelling
Karin
K
D001483:Base Sequence; D002478:Cells, Cultured; D004279:DNA, Viral / Q000235:genetics; D024882:Drug Resistance, Viral; D004789:Enzyme Activation / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000302:isolation & purification* / Q000472:pathogenicity; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology*; D012367:RNA, Viral / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D016914:Ribonuclease H / Q000378:metabolism*; D019562:Viral Load; D014771:Virion / Q000472:pathogenicity; D038301:Virus Inactivation
D004279:DNA, Viral; D016376:Oligonucleotides, Antisense; D012367:RNA, Viral; D016914:Ribonuclease H