ABSTRACT
Two groups of the antiviral agents: 1) adamantane- and norbornen-containing compounds with in-built cholesterol to potentiate the membranotropic properties and 2) synthetic matrix protein peptides (peptides A and B) were found to have effects on HIV replication. The agents of the former group produced antiviral activity only when added in combination with the virus. Peptide A (matrix protein 43-60 amino acids) inhibited viral replication when added in both the early and late periods. Fluorescein-labeled peptide A was detectable in the cytoplasm and nucleus (although adsorption of a portion of the peptides cannot be excluded onto the cell surface). Peptide A was shown to inhibit Gag precursor p55 transport from the nuclei to the plasma membrane, the site of virus assembly. Peptide B had no antiviral activity.
Subject(s)
Adamantane/pharmacology , Anti-HIV Agents/pharmacology , HIV-1/drug effects , Norbornanes/pharmacology , Oncogene Protein pp60(v-src)/pharmacology , Peptide Fragments/pharmacology , Virus Replication/drug effects , Cell Line, Tumor , HIV-1/physiology , Humans , Protein Precursors/antagonists & inhibitors , Protein Precursors/metabolism , Protein Transport/drug effectsABSTRACT
Much progress has been recently made in research of the final stages of the HIV-1 life cycle, i.e. of its assembly, gemmation and maturation. The virus was shown, in particular, to use widely cell mechanisms in its replication and assembly. The TSG 101 cellular endosomal sorting protein interacting with the p6 viral protein is necessary for gemmation. Cyclophilin and HP68 (cell proteins) needed for marphogenesis of the virus were identified. The recently obtained data on the interaction of Vif (a viral protein) and Apobec (a cell protein) showed that HIV-1 has an action mechanism overcoming the cell barriers. The "early" virus phenomenon, which is deprived of any mature structure or the ability to infect and does not contain mature Gag and Env proteins, illustrates that the proteolytic pressing of the Gag p55 precursor is not enough for the maturation of the virus and additional viral or cellular factors are needed for the virus to become infectious. Although the current antiviral therapy has been successful enough, it is far from being effective in all cases; one of the reasons is resistance to chemodrugs developing rapidly in patients. Fast mutations and exceptional plasticity of the viral genome (which helps the virus to develop rapidly resistance to drugs) belong to the major problems. The circulation of persistent virus variants has been quickly increasing. There is an urgent need in developing new antiviral drugs acting on new viral targets; progress in experimental virology would speed it up. Thus, new drugs can be created, which block the activity of Vif, that would make Apobec block the virus replication. Compounds can be developed, which block the interaction of cyclophilin and TSG101 with viral proteins. The recently described importance of cholesterol in the sexual transfer of viruses is expected to bring simple and inexpensive compounds destroying cholesterol in the mucous tunic of genitals into clinical use. The identification of additional factors needed for the maturation of the virus and for its becoming infectious can be a basis for the development of drugs blocking their packaging into virions. Future research is expected to define new targets for the chemotherapy of AIDS and to promote the designing of new chemodrugs.
