Manganese cations increase the mutation rate of human immunodeficiency virus type 1 ex vivo

Human immunodeficiency virus (HIV) reverse transcription is an error-prone process with an overall mutation rate of approximately 3.4 x 10(-5) per base per replication cycle. This rate can be modulated by changes in different components of the retrotranscription reaction. In particular, in vitro substitution of magnesium cations (Mg2+) by manganese cations (Mn2+) has been shown to increase misincorporation of deoxynucleotide triphosphates (dNTPs) and to alter substrate specificity. Here, it is shown that Mn2+ also increases the HIV mutation rate ex vivo. Treatment of permissive cells with Mn2+ and subsequent HIV infection resulted in at least 6-fold and 10-fold increases in the mutant and mutation frequencies respectively, thus illustrating a further example of how to influence HIV genetic variation.