title: Increased mutation frequency of feline immunodeficiency virus lacking functional deoxyuridine-triphosphatase.
abstract: 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 approximately 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.
authors.affiliation: Department of Molecular Biology, Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Lerner
authors.forename: P C
authors.initials: PC
authors.lastname: Wagaman
authors.forename: T R
authors.initials: TR
authors.lastname: Phillips
authors.forename: O
authors.initials: O
authors.lastname: Prospero-Garcia
authors.forename: S J
authors.initials: SJ
authors.lastname: Henriksen
authors.forename: H S
authors.initials: HS
authors.lastname: Fox
authors.forename: F E
authors.initials: FE
authors.lastname: Bloom
authors.forename: J H
authors.initials: JH
authors.lastname: Elder
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002213:Capsid / Q000235:genetics / Q000276:immunology; D002415:Cats; D017931:DNA Primers / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D016181:Feline Acquired Immunodeficiency Syndrome / Q000821:virology; D015751:Genes, pol; D016679:Genome, Viral; D016089:Immunodeficiency Virus, Feline / Q000201:enzymology* / Q000235:genetics* / Q000254:growth & development; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D011755:Pyrophosphatases / Q000235:genetics*; D014018:Tissue Distribution
chemical_list: D017931:DNA Primers; D004279:DNA, Viral; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase