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

Danica L. Lerner, Pamela C. Wagaman, Tom R. Phillips, Oscar Prospero-Garcia, Steven J. Henriksen, Howard S. Fox, Floyd E. Bloom, John H. Elder

Research output: Contribution to journalArticle

86 Citations (Scopus)

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 ≃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.

Original languageEnglish (US)
Pages (from-to)7480-7484
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume92
Issue number16
DOIs
StatePublished - Aug 1 1995

Fingerprint

Feline Immunodeficiency Virus
Deoxyuridine
Mutation Rate
Cats
Primate Lentiviruses
Macrophages
pol Genes
Viruses
Specific Pathogen-Free Organisms
Integrases
Mutation
RNA-Directed DNA Polymerase
DNA
Viral DNA
Tissue Distribution
Enzymes
Virus Replication
Infection
Salivary Glands
Reverse Transcription

Keywords

  • dUTPase
  • feline
  • immunodeficiency
  • lentivirus
  • misincorporation

ASJC Scopus subject areas

  • General

Cite this

Increased mutation frequency of feline immunodeficiency virus lacking functional deoxyuridine-triphosphatase. / Lerner, Danica L.; Wagaman, Pamela C.; Phillips, Tom R.; Prospero-Garcia, Oscar; Henriksen, Steven J.; Fox, Howard S.; Bloom, Floyd E.; Elder, John H.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 92, No. 16, 01.08.1995, p. 7480-7484.

Research output: Contribution to journalArticle

Lerner, Danica L. ; Wagaman, Pamela C. ; Phillips, Tom R. ; Prospero-Garcia, Oscar ; Henriksen, Steven J. ; Fox, Howard S. ; Bloom, Floyd E. ; Elder, John H. / Increased mutation frequency of feline immunodeficiency virus lacking functional deoxyuridine-triphosphatase. In: Proceedings of the National Academy of Sciences of the United States of America. 1995 ; Vol. 92, No. 16. pp. 7480-7484.
@article{98ab1bbfecef406690cdf895354288bf,
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 ≃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.",
keywords = "dUTPase, feline, immunodeficiency, lentivirus, misincorporation",
author = "Lerner, {Danica L.} and Wagaman, {Pamela C.} and Phillips, {Tom R.} and Oscar Prospero-Garcia and Henriksen, {Steven J.} and Fox, {Howard S.} and Bloom, {Floyd E.} and Elder, {John H.}",
year = "1995",
month = "8",
day = "1",
doi = "10.1073/pnas.92.16.7480",
language = "English (US)",
volume = "92",
pages = "7480--7484",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "16",

}

TY - JOUR

T1 - Increased mutation frequency of feline immunodeficiency virus lacking functional deoxyuridine-triphosphatase

AU - Lerner, Danica L.

AU - Wagaman, Pamela C.

AU - Phillips, Tom R.

AU - Prospero-Garcia, Oscar

AU - Henriksen, Steven J.

AU - Fox, Howard S.

AU - Bloom, Floyd E.

AU - Elder, John H.

PY - 1995/8/1

Y1 - 1995/8/1

N2 - 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.

AB - 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.

KW - dUTPase

KW - feline

KW - immunodeficiency

KW - lentivirus

KW - misincorporation

UR - http://www.scopus.com/inward/record.url?scp=0029153930&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0029153930&partnerID=8YFLogxK

U2 - 10.1073/pnas.92.16.7480

DO - 10.1073/pnas.92.16.7480

M3 - Article

C2 - 7638216

AN - SCOPUS:0029153930

VL - 92

SP - 7480

EP - 7484

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 16

ER -