The Impact of dNTP Concentrations on the Early Stages of HIV-1 Transduction

dNTPs are small cellular metabolites utilized by a host cell for the maintenance and replication of chromosomal DNA. In cells that do not require DNA replication, such as macrophages, the concentration of these metabolites is very limited. HIV-1 also utilizes these metabolites for the reverse transcription and integration of proviral DNA. Additionally, many viral inhibitors are designed to mimic natural dNTPs. It has been previously shown that a limited cellular dNTP concentration can restrict HIV-1 tropism. This occurs when certain key elements within the virus are mutated, such as the reverse transcriptase (RT) mutant Q151N, or the central polypurine tract (cPPT). However, many residues within reverse transcriptase, as well as their interactions with dNTPs and the interplay with the cPPT still remain to be elucidated. Additionally, the effect of low dNTP concentrations on viral integration remains unknown. Here we report that mutations of the RT residue A114 alter the ability of this enzyme to bind dNTPs. Additionally, a mechanistic interplay exists between the RT mutation M184I, the cPPT and dNTPs. Furthermore, viral integration and 5'-end gap repair relies on a high dNTP concentration for completion.