Sequence variations in HIV-1 and HIV-2 probably result in part from inaccurate DNA synthesis by viral reverse transcriptases (RTs). We have studied in vitro the fidelity of both the DNA- and RNA-dependent DNA polymerization functions of the two HIV RTs, as compared to that of murine leukemia virus (MLV) RT. The two HIV RTs were less accurate than MLV RT. The mispair extension frequencies observed previously with ribosomal RNA (rRNA) template were higher than those detected with ØX174am3 DNA template with all three RTs. In the current study we have investigated whether the nature of the copied nucleic acid (RNA vs. DNA) or the template nucleotide sequences affect the accuracy of DNA synthesis. We have analyzed the fidelity of DNA synthesis with DNA sequences identical to those of the rRNA sequences previously employed for reverse transcription. The results indicate that the fidelity of DNA synthesis depends mainly on the nucleotide sequences copied by every given RT. Yet, fidelity of DNA synthesis depends not only on the sequences copied but also on the nature of the enzymes per se. It is possible that these factors are major contributors to the high mutation rates of the two human immunodeficiency viruses.
