Abstract
BackgroundHIV is primarily transmitted by sexual intercourse and predominantly infects people in Third World countries. Here an important medical need is self-protection for women, particularly in societies where condoms are not widely accepted. Therefore, availability of antiviral microbicides may significantly reduce sexual HIV transmission in such environments.MethodsHere, we investigated structural characteristics and the antiviral activity of the polypurine tract (PPT)-specific ODN A, a 54-mer oligodeoxynucleotide (ODN) that has been previously shown to trigger the destruction of viral RNA genomes by prematurely activating the retroviral RNase H. The stability of ODN A and mutants thereof was tested at various storage conditions. Furthermore, antiviral effects of ODN A were analyzed in various tissue culture HIV-1 infection models. Finally, circular dichroism spectroscopy was employed to gain insight into the structure of ODN A.ResultsWe show here that ODN A is a powerful tool to abolish HIV-1 particle infectivity, as required for a candidate compound in vaginal microbicide applications. We demonstrate that ODN A is not only capable to prematurely activate the retroviral RNase H, but also prevents HIV-1 from entering host cells. ODN A also exhibited extraordinary stability lasting several weeks. Notably, ODN A is biologically active under various storage conditions, as well as in the presence of carboxymethylcellulose CMC (K-Y Jelly), a potential carrier for application as a vaginal microbicide. ODN A’s remarkable thermostability is apparently due to its specific, guanosine-rich sequence. Interestingly, these residues can form G-quadruplexes and may lead to G-based DNA hyperstructures. Importantly, the pronounced antiviral activity of ODN A is maintained in the presence of human semen or semen-derived enhancer of virus infection (SEVI; i.e. amyloid fibrils), both known to enhance HIV infectivity and reduce the efficacy of some antiviral microbicides.ConclusionsSince ODN A efficiently inactivates HIV-1 and also displays high stability and resistance against semen, it combines unique and promising features for its further development as a vaginal microbicide against HIV.
Highlights
HIV is primarily transmitted by sexual intercourse and predominantly infects people in Third World countries
We previously described ODN A, a novel oligonucleotidebased HIV-1 inhibitor that targets the highly-conserved extended polypurine tract (PPT) of HIV-1 for subsequent RNase H-dependent degradation of the viral RNA genome in cell-free HIV-1 particles [11,12,13]
The ODN A sequence is partially complementary to the extended HIV-1 polypurine tract (PPT), ODN Co targets a region downstream of the PPT and, compared to ODN A, ODN G contains some nucleotide exchanges in the antisense strand to prevent binding to the HIV-1 PPT, whereas the passenger strand is identical (Fig. 1)
Summary
HIV is primarily transmitted by sexual intercourse and predominantly infects people in Third World countries. An important medical need is self-protection for women, in societies where condoms are not widely accepted. Availability of antiviral microbicides may significantly reduce sexual HIV transmission in such environments. Infection with HIV-1 is a global pandemic that affects Third World countries. HIV is transmitted primarily by sexual intercourse and in 2013 more than 35 million people globally were living with HIV. Over 70 % of infected subjects reside in Sub-Saharan Africa, with enormous medical and socioeconomic consequences for these societies. Use of condoms is frequently not accepted by men in some of these societies. Development of novel microbicides is of urgent medical need, but would empower women with a means for self-protection
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