Inhibition of HIV-1 reverse transcription by triple-helix forming oligonucleotides with viral RNA

Volkmann, Silke; Jendis, Jörg; Frauendorf, Albrecht; Moelling, Karin

doi:10.1093/nar/23.7.1204

Cited by 46 publications

(16 citation statements)

References 31 publications

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“…In HIV, triple strand formation of an RNA-DNA hybrid with DNA or RNA oligonucleotides inhibits RNase H cleavage and initiation of plus-strand DNA synthesis in vitro. In cell culture experiments, the addition of the triple-strand-forming oligonucleotide efficiently inhibits retrovirus replication indicating that the triple strand can also be formed in vivo [135]. The triple strand approach may also be useful in plant systems.…”

Section: Triple Helicesmentioning

confidence: 99%

RNA structure and the regulation of gene expression

1996

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RNA secondary and tertiary structure is involved in post-transcriptional regulation of gene expression either by exposing specific sequences or through the formation of specific structural motifs. An overview of RNA secondary and tertiary structures known from biophysical studies is followed by a review of examples of the elements of RNA processing, mRNA stability and translation of the messenger. These structural elements comprise sense-antisense double-stranded RNA, hairpin and stem-loop structures, and more complex structures such as bifurcations, pseudoknots and triple-helical elements. Metastable structures formed during RNA folding pathway are also discussed. The examples presented are mostly chosen from plant systems, plant viruses, and viroids. Examples from bacteria or fungi are discussed only when unique regulatory properties of RNA structures have been elucidated in these systems.

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Section: Triple Helicesmentioning

confidence: 99%

RNA structure and the regulation of gene expression

1996

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“…The two‐strand system comprises a Watson‐Crick and Hoogsteen base‐pairing sequence on a single strand connected by one hairpin loop (T) 5. These are referred to as foldback triplex‐forming oligonucleotides (FTFOs) [14–20]. The formation of the pyr/pur/pyr triple‐helix, which is pH‐dependent and unstable under physiological conditions, was avoided by the substitution of G for C + in the third Hoogsteen base‐pairing strand.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of HIV‐1 replication by a two‐strand system (FTFOs) targeted to the polypurine tract

et al. 1999

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Reverse transcription of HIV-1 vRNA into the double-stranded DNA provirus involves initiation of plus-strand DNA synthesis at the polypurine tract (PPT) by reverse transcriptase (RT). The PPT is highly conserved among the known human immunodeficiency virus (HIV-1) strains and is a possible target for triplex formation. We show the effects of triple-helix formation by assays of primer extension inhibition in vitro, using a two-strand system (foldback triplex-forming oligonucleotides (FTFOs)) targeted to the PPT of HIV-1. The two-stranded composition of a triple-helix is thermodynamically and kinetically superior to the three-strand system. The FTFOs inhibited the RT activity in a sequence-specific manner, i.e. the triplex actually formed at the PPT and blocked the RT. The FTFOs containing the phosphorothioate groups at the antisense sequences showed greater 3P P-exonuclease resistance. In HIV-1-infected MOLT-4 cells, the FTFOs containing the phosphorothioate groups at the antisense sequence sites and guanosine rich parts within the third Hoogsteen base-pairing sequence inhibit the replication of HIV-1 more effectively than the antisense oligonucleotides, indicating sequence-specific inhibition of HIV-1 replication.z 1999 Federation of European Biochemical Societies.

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“…For removal of the two primers, cuts occur at RNA-DNA junctions opposite to the DNA strand. 1,5,11 Cleavage at the PPT is highly specific, because it will lead to the dinucleotides required for integration by the viral integrase into the host DNA genome. 1,5 The RNase H itself cleaves nonspecifically, but sequence specificity is dictated by the polymerase domain and the distance between the two active centers between the RT and the RNase H. This distance is 18 nucleotides and, consequently, the length of the primer at the PBS is 18 nucleotides, as is the cleavage site at the PPT.…”

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Premature Activation of the HIV RNase H Drives the Virus into Suicide: A Novel Microbicide?

Broecker

Andrae

Moelling

2012

AIDS Research and Human Retroviruses

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Sexual transmission of HIV is the major cause of spread of HIV in Africa and the Third World and is an unmet medical need. Recently, microbicides have attracted attention because they allow females to protect themselves and their offspring. We are exploiting one of the four retroviral enzymes, the ribonuclease H, RNase H, as a novel approach for a microbicide. It is the only enzyme of HIV not yet targeted by antiretroviral therapy. The enzyme is linked to the reverse transcriptase (RT) and hydrolyzes the RNA moiety of RNA-DNA hybrids. The RNase H is located inside virus particles and normally functions during viral replication inside cells. Here we show that activating the RNase H prematurely inside the virus particles destroys the viral genome and abrogates viral infectivity. The antiviral compound consists of a synthetic oligodeoxynucleotide (ODN), which creates an artificial RNA-DNA hybrid substrate for the RNase H inside the particle. The compound was analyzed in mouse models including humanized SCID mice and the vagina of mice. Infection was reduced up to 1000-fold or could be completely prevented. The compound is suitable as microbicide or to prevent mother-to-child transmission.

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Inhibition of HIV-1 reverse transcription by triple-helix forming oligonucleotides with viral RNA

Cited by 46 publications

References 31 publications

RNA structure and the regulation of gene expression

RNA structure and the regulation of gene expression

Inhibition of HIV‐1 replication by a two‐strand system (FTFOs) targeted to the polypurine tract

Premature Activation of the HIV RNase H Drives the Virus into Suicide: A Novel Microbicide?

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