INCREASED MUTATION FREQUENCY OF FELINE IMMUNODEFICIENCY VIRUS LACKINGFUNCTIONAL DEOXYURIDINE-TRIPHOSPHATASE

Feline immunodeficiency virus (FIV) encodes the enzyme deoxyuridine-tr iphosphatase (DU; EC 3.6.1.23) between the coding regions for reverse transcriptase and integrase in the Pol gene. Here, we report the in vi vo infection of cats with a DU- variant of the PPR strain of FIV and c ompare its growth properties and tissue distribution with those of wil d-type FIV-PPR, The results reveal several important points: (i) DU- F IV is able to infect the cat, with kinetics similar to that observed w ith wild-type FIV; (ii) both wild-type and DU- FIV-infected specific-p athogen free cats mount a strong humoral antibody response which is ab le to limit the virus burden in both groups of animals; (iii) the viru s burden is reduced in the DU- FIV-infected cats, particularly in tiss ues such as spleen and salivary gland; and (iv) the mutation frequency in DU- FIVs integrated in the DNA of primary macrophages after 9 mont hs of infection is approximate to 5-fold greater than the frequency ob served in DU- FIV DNA integrated in T lymphocytes, Mutation rate with wild-type FIV remains the same in both cell types in vivo. The dominan t mutations seen in macrophages with DU- FIV are G --> A base changes, consistent with an increased misincorporation of deoxyuridine into vi ral DNA of DU- FIVs during reverse transcription, Because this enzyme is absent from human immunodeficiency virus type 1 and other primate l entiviruses, virus replication in cell environments with low DU activi ty may lead to increased mutation and contribute to the rapid expansio n of the viral repertoire.