Inhibition of the activities of reverse transcriptase and integrase of human immunodeficiency virus type-1 by peptides derived from the homologous viral protein R (Vpr).

Shortly after infection by human immunodeficiency virus (HIV), two complexes are formed in a stepwise manner in the cytoplasm of infected cells: the reverse transcription complex that later becomes the preintegration complex. Both complexes include, in addition to cellular proteins, viral RNA or DNA and several proteins, such as reverse transcriptase (RT), integrase (IN), and viral protein R (Vpr). These proteins are positioned in close spatial proximity within these complexes, enabling mutual interactions between the proteins. Physical in vitro interactions between RT and IN that affect their enzymatic activities were already reported. Moreover, we found recently that HIV-1 RT-derived peptides bind and inhibit HIV-1 IN and that an IN-derived peptide binds and inhibits HIV-1 RT. Additionally, HIV-1 Vpr and its C-terminal domain affected in vitro the integration activity of HIV-1 IN. Here, we describe the associations of Vpr-derived peptides with RT and IN. Of a peptide library that spans the 96-residue-long Vpr protein, three partially overlapping peptides, derived from the C-terminal domain, bind both enzymes. Two of these peptides inhibit both RT and IN. Another peptide, derived from the Vpr N-terminal domain, binds IN and inhibits its activities, without binding and affecting RT. Interestingly, two sequential C-terminal peptides (derived from residues 57-71 and 61-75 of full-length Vpr) are the most effective inhibitors of both enzymes. The data and the molecular modeling presented suggest that RT and IN are inhibited as a result of steric hindrance or conformational changes of their active sites, whereas a second mechanism of blocking its dimerization state could be also attributed to the inhibition of IN.