Increased mutation frequency of feline immunodeficiency virus lacking functional deoxyuridine-triphosphatase

Feline immunodeficiency virus (FIV) encodes the enzyme deoxyuridine- triphosphatase (DU; EC 3.6.1.23) between the coding regions for reverse transcriptase and integrase in the pol gene. Here, we report the in vivo infection of cats with a DU^- variant of the PPR strain of FIV and compare its growth properties and tissue distribution with those of wild-type FIV- PPR. The results reveal several important points: (i) DU^- FIV is able to infect the cat, with kinetics similar to that observed with wild-type FIV; (ii) both wild-type and DU^- FIV-infected specific-pathogen free cats mount a strong humoral antibody response which is able to limit the virus burden in both groups of animals; (iii) the virus burden is reduced in the DU^- FIV- infected cats, particularly in tissues such as spleen and salivary gland; and (iv) the mutation frequency in DU^- FIVs integrated in the DNA of primary macrophages after 9 months of infection is ≃5-fold greater than the frequency observed in DU^- FIV DNA integrated in T lymphocytes. Mutation rate with wild-type FIV remains the same in both cell types in vivo. The dominant mutations seen in macrophages with DU^- FIV are G → A base changes, consistent with an increased misincorporation of deoxyuridine into viral DNA of DU^- FIVs during reverse transcription. Because this enzyme is absent from human immunodeficiency virus type 1 and other primate lentiviruses, virus replication in cell environments with low DU activity may lead to increased mutation and contribute to the rapid expansion of the viral repertoire.