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Human papillomavirus induces the hyperproliferation of epithelial cells, leading to a broad spectrum of human diseases, ranging from benign warts to malignant neoplasms, depending on the location of the lesion, the immune status of the patient and the type of human papillomavirus. Current therapies for human papillomavirus-associated diseases are based on the excision or ablation of dysplastic or malignant tissue, and are associated with a high frequency of recurrent disease, discomfort and costs. A better understanding of the viral replicative cycle and of the interaction between the virus and the host cell, particularly the cell cycle regulation, has opened new perspectives. Recently, new treatment modalities for human papillomavirus-induced lesions have been identified, including the use of antiviral/immunomodulatory therapies, such as cidofovir, antisense oligonucleotides, imiquimod and human papillomavirus vaccines.
Abstract (XII).
Inhibitors interfering with human immunodeficiency virus (HIV) gene regulation may have great potential in anti-HIV drug (combination) therapy. They act against different targets to currently used anti-HIV drugs, reduce virus production from acute and chronically infected cells and are anticipated to elicit less virus drug resistance. Several agents have already proven to inhibit HIV gene regulation in vitro. A first class of compounds interacts with cellular factors that bind to the long terminal repeat (LTR) promoter and that are needed for basal level transcription, such as NF-kappa B and Sp1 inhibitors. A second class of compounds specifically inhibits the transactivation of the HIV LTR promoter by the viral Tat protein, such as the peptoid CGP64222. A third class of compounds prevents the accumulation of single and unspliced mRNAs through inhibition of the viral regulator protein Rev, such as the aminoglycosidic antibiotics. Most of these compounds have been tested in specific transactivation assays. Whether they are active at the postulated target in virus replication assays has, for many of them, not been ascertained. Toxicity data are often lacking or insufficient. Yet these data are crucial in view of the toxicity that may be expected for compounds that primarily interact with cellular factors. Although a promising lead, considerable research is still required before gene regulation inhibitors may come of age as clinically useful agents.
Although the presence of free 2′‐hydroxyl groups in both strands of a double‐stranded RNA complex has been recognized as one of the major requisites for the interferon‐inducing activity of double‐stranded RNAs, we have found a particular analogue of (I) n · (C) n in which the 2′‐hydroxyls of the purine nucleotide strand were replaced by azido groups, (dIn 3 ) n · (C) n , to be highly effective in inducing interferon. Various other 2′‐azido analogues of (I) n · (C) n and (A) n · (U) n , i.e. (dIn 3 ) n · (br 5 C) n , (I) n · (dCn 3 ) n , (dAn 3 ) n · (U) n , (A) n · (dUn 3 ) n , (dAn 3 ) n · (rT) n and (dAn 3 ) n · (dUn 3 ) n , were inactive as inducers of interferon. In human fibroblast cultures, the interferon‐inducing activity of (dIn 3 ) n · (C) n equalled that of (I) n · (C) n . In other interferon‐induction systems (primary rabbit kidney cells, mouse L‐929 cells, intact rabbits), (dIn 3 ) n · (C) n was less active than (I) n · (C) n . As assessed by both radio‐chemical and biological means, (dIn 3 ) n · (C) n was more susceptible to degradation by pancreatic ribonuclease and human serum nucleases than was (I) n · (C) n . The t m of (dIn 3 ) n · (C) n was 52.5 °C, as compared to 62.5 °C for (I) n · (C) n , both determined in 0.15 M Na + , pH 7.0. Under the same conditions, (dIn 3 ) n · (br 5 C) n had a t m of 77 °C and (I) n · (br 5 C) n had a t m of 87 °C. The reactivity of (dIn 3 ) n · (C) n and (dIn 3 ) n · (br 5 C) n towards antibodies to double‐stranded RNA was evaluated by quantitative complement fixation, counterimmunoelectrophoresis and competitive radioimmunoassay. In these tests, (dIn 3 ) n · (C) n and (dIn 3 ) n · (br 5 C) n showed an immunoreactivity pattern comparable to that of (I) n · (C) n and (I) n · (br 5 C) n .
No abstract is provided for this article.
Of the different steps of the HIV replicative cycle, the reverse transcription step has received most attention as a target for chemotherapeutic intervention. The reverse transcriptase (RT) can be blocked by both nucleoside (nucleotide) and non-nucleoside type of inhibitors. Whereas the former act as competitive inhibitors with respect to the natural substrates or alternate substrates (chain terminators), the latter act allosterically with a non-substrate binding site of the enzyme. Several non-nucleoside types of RT inhibitors have proved to inhibit HIV-1 replication at nanomolar concentrations that are 10(4)- to 10(5)-fold lower than the cytotoxic concentrations. Although a non-nucleoside HIV-1-specific RT inhibitor may rapidly select for virus-drug resistance in cell culture, the resulting mutant strain may or may not show cross-resistance, and in some instances even hypersensitivity, to other HIV-specific RT inhibitors. When used at the appropriate concentrations, HIV-1-specific RT inhibitors are able to completely shut off ("knock-out") virus replication in vitro, under conditions where dideoxynucleoside analogues such as AZT fail to do so. This apparent "sterilizing effect" achieved by the non-nucleoside type of HIV-1-specific RT inhibitors opens new perspectives for the treatment of HIV infections in patients.
