Regulation of the HIV-1 integrase activity by the viral Rev protein: The effect of cell permeable peptides derived from the integrase and Rev proteins

The Human Immunodefi ciency Virus (HIV) has caused the death of over 25 million people, worldwide, since 1981. Today 33.4 to 46 million people are infected with HIV and the numbers are rapidly increasing. Two types of HIV are known to infect humans; HIV-1 and HIV-2. HIV-1 is the more common of the two and the one that causes the larger number of fatalities. An essential step in the replication cycle of all retroviruses is the integration of the viral DNA (after reverse transcription) into the host genome. The research set forth here deals with the molecular mechanisms of the integrase (IN) activity and its regulation. The HIV-1 IN mediates the integration of the viral genome into the host cell DNA. In HIV-1 infected cells there are only one or two integrated viral genomes (proviruses) per cell while in other retroviruses the number of proviruses per cell is much higher. The mechanism which prevents multiple integrations is specifi c to HIV-1 and is yet unknown. Thus elucidation of the detailed mechanism of the regulation of IN activity may lead not only to a better understanding of the viral replication cycle but also to the development of new anti-HIV-1 drugs. We suggest that one of the HIV-1 early translated proteins, namely the Rev protein, may be responsible for this regulation. The viral Rev protein, mediates nuclear export of viral un-spliced and partially spliced RNA. We have observed that Rev binds to IN and furthermore it inhibits the IN activity in-vitro. These results may indicate that the Rev protein may regulate the enzymatic activity of the IN and consequently the viral DNA integration process. Support of this view obtained from results showing that Rev derived peptides are able to inhibit the IN activity in-vitro and in-vivo while peptides derived from the IN, which binds to the Rev, abrogate those inhibitions and increase the IN activity in cell cultures