Human immunodeficiency virus-1 tropism highly correlates with the amino acid (aa) composition of the third hypervariable region (V3) of gp120. A shift towards more positively charged aa is seen when binding to CXCR4 compared with CCR5 (X4 vs. R5 strains), especially positions 11 and 25 (11/25-rule) predicting X4 viruses in the presence of positively charged residues. At nucleotide levels, negatively or uncharged aa, e.g., aspartic and glutamic acid and glycine, which are encoded by the triplets GAN (guanine-adenosine-any nucleotide) or GGN are found more often in R5 strains. Positively charged aa such as arginine and lysine encoded by AAR or AGR (CGN) (R means A or G) are seen more frequently in X4 strains suggesting our hypothesis that a switch from R5 to X4 strains occurs via a G-to-A mutation. 1527 V3 sequences from three independent data sets of X4 and R5 strains were analysed with respect to their triplet composition. A higher number of G-containing triplets was found in R5 viruses, whereas X4 strains displayed a higher content of A-comprising triplets. These findings also support our hypothesis that G-to-A mutations are leading to the co-receptor switch from R5 to X4 strains. Causative agents for G-to-A mutations are the deaminases APOBEC3F and APOBEC3G. We therefore hypothesize that these proteins are one driving force facilitating the appearance of X4 variants. G-to-A mutations can lead to a switch from negatively to positively charged aa and a respective alteration of the net charge of gp120 resulting in a change of co-receptor usage.