Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1995 Aug 1;92(16):7480–7484. doi: 10.1073/pnas.92.16.7480

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

D L Lerner 1, P C Wagaman 1, T R Phillips 1, O Prospero-Garcia 1, S J Henriksen 1, H S Fox 1, F E Bloom 1, J H Elder 1
PMCID: PMC41363  PMID: 7638216

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.

Full text

PDF
7480

Images in this article

7482Fig. 2
on p.7482

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Borghi P., Fantuzzi L., Varano B., Gessani S., Puddu P., Conti L., Capobianchi M. R., Ameglio F., Belardelli F. Induction of interleukin-10 by human immunodeficiency virus type 1 and its gp120 protein in human monocytes/macrophages. J Virol. 1995 Feb;69(2):1284–1287. doi: 10.1128/jvi.69.2.1284-1287.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Dow S. W., Dreitz M. J., Hoover E. A. Feline immunodeficiency virus neurotropism: evidence that astrocytes and microglia are the primary target cells. Vet Immunol Immunopathol. 1992 Dec;35(1-2):23–35. doi: 10.1016/0165-2427(92)90118-a. [DOI] [PubMed] [Google Scholar]
  3. Elder J. H., Lerner D. L., Hasselkus-Light C. S., Fontenot D. J., Hunter E., Luciw P. A., Montelaro R. C., Phillips T. R. Distinct subsets of retroviruses encode dUTPase. J Virol. 1992 Mar;66(3):1791–1794. doi: 10.1128/jvi.66.3.1791-1794.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Elder J. H., Phillips T. R. Feline immunodeficiency virus as a model for development of molecular approaches to intervention strategies against lentivirus infections. Adv Virus Res. 1995;45:225–247. doi: 10.1016/s0065-3527(08)60062-7. [DOI] [PubMed] [Google Scholar]
  5. Fisher F. B., Preston V. G. Isolation and characterisation of herpes simplex virus type 1 mutants which fail to induce dUTPase activity. Virology. 1986 Jan 15;148(1):190–197. doi: 10.1016/0042-6822(86)90414-9. [DOI] [PubMed] [Google Scholar]
  6. Folks T. M., Justement J., Kinter A., Dinarello C. A., Fauci A. S. Cytokine-induced expression of HIV-1 in a chronically infected promonocyte cell line. Science. 1987 Nov 6;238(4828):800–802. doi: 10.1126/science.3313729. [DOI] [PubMed] [Google Scholar]
  7. Garvey K. J., Oberste M. S., Elser J. E., Braun M. J., Gonda M. A. Nucleotide sequence and genome organization of biologically active proviruses of the bovine immunodeficiency-like virus. Virology. 1990 Apr;175(2):391–409. doi: 10.1016/0042-6822(90)90424-p. [DOI] [PubMed] [Google Scholar]
  8. Koenig S., Gendelman H. E., Orenstein J. M., Dal Canto M. C., Pezeshkpour G. H., Yungbluth M., Janotta F., Aksamit A., Martin M. A., Fauci A. S. Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science. 1986 Sep 5;233(4768):1089–1093. doi: 10.1126/science.3016903. [DOI] [PubMed] [Google Scholar]
  9. Koyanagi Y., O'Brien W. A., Zhao J. Q., Golde D. W., Gasson J. C., Chen I. S. Cytokines alter production of HIV-1 from primary mononuclear phagocytes. Science. 1988 Sep 23;241(4873):1673–1675. doi: 10.1126/science.241.4873.1673. [DOI] [PubMed] [Google Scholar]
  10. Martinez M. A., Vartanian J. P., Wain-Hobson S. Hypermutagenesis of RNA using human immunodeficiency virus type 1 reverse transcriptase and biased dNTP concentrations. Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):11787–11791. doi: 10.1073/pnas.91.25.11787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. McClure M. A., Johnson M. S., Doolittle R. F. Relocation of a protease-like gene segment between two retroviruses. Proc Natl Acad Sci U S A. 1987 May;84(9):2693–2697. doi: 10.1073/pnas.84.9.2693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. McClure M. A., Johnson M. S., Feng D. F., Doolittle R. F. Sequence comparisons of retroviral proteins: relative rates of change and general phylogeny. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2469–2473. doi: 10.1073/pnas.85.8.2469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. McGeoch D. J. Protein sequence comparisons show that the 'pseudoproteases' encoded by poxviruses and certain retroviruses belong to the deoxyuridine triphosphatase family. Nucleic Acids Res. 1990 Jul 25;18(14):4105–4110. doi: 10.1093/nar/18.14.4105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Pedersen N. C., Ho E. W., Brown M. L., Yamamoto J. K. Isolation of a T-lymphotropic virus from domestic cats with an immunodeficiency-like syndrome. Science. 1987 Feb 13;235(4790):790–793. doi: 10.1126/science.3643650. [DOI] [PubMed] [Google Scholar]
  15. Phillips T. R., Prospero-Garcia O., Puaoi D. L., Lerner D. L., Fox H. S., Olmsted R. A., Bloom F. E., Henriksen S. J., Elder J. H. Neurological abnormalities associated with feline immunodeficiency virus infection. J Gen Virol. 1994 May;75(Pt 5):979–987. doi: 10.1099/0022-1317-75-5-979. [DOI] [PubMed] [Google Scholar]
  16. Phillips T. R., Talbott R. L., Lamont C., Muir S., Lovelace K., Elder J. H. Comparison of two host cell range variants of feline immunodeficiency virus. J Virol. 1990 Oct;64(10):4605–4613. doi: 10.1128/jvi.64.10.4605-4613.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Podell M., Oglesbee M., Mathes L., Krakowka S., Olmstead R., Lafrado L. AIDS-associated encephalopathy with experimental feline immunodeficiency virus infection. J Acquir Immune Defic Syndr. 1993 Jul;6(7):758–771. [PubMed] [Google Scholar]
  18. Poli G., Bressler P., Kinter A., Duh E., Timmer W. C., Rabson A., Justement J. S., Stanley S., Fauci A. S. Interleukin 6 induces human immunodeficiency virus expression in infected monocytic cells alone and in synergy with tumor necrosis factor alpha by transcriptional and post-transcriptional mechanisms. J Exp Med. 1990 Jul 1;172(1):151–158. doi: 10.1084/jem.172.1.151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Power M. D., Marx P. A., Bryant M. L., Gardner M. B., Barr P. J., Luciw P. A. Nucleotide sequence of SRV-1, a type D simian acquired immune deficiency syndrome retrovirus. Science. 1986 Mar 28;231(4745):1567–1572. doi: 10.1126/science.3006247. [DOI] [PubMed] [Google Scholar]
  20. Preston V. G., Fisher F. B. Identification of the herpes simplex virus type 1 gene encoding the dUTPase. Virology. 1984 Oct 15;138(1):58–68. doi: 10.1016/0042-6822(84)90147-8. [DOI] [PubMed] [Google Scholar]
  21. Prospéro-García O., Herold N., Phillips T. R., Elder J. H., Bloom F. E., Henriksen S. J. Sleep patterns are disturbed in cats infected with feline immunodeficiency virus. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12947–12951. doi: 10.1073/pnas.91.26.12947. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Prospéro-García O., Herold N., Waters A. K., Phillips T. R., Elder J. H., Henriksen S. J. Intraventricular administration of a FIV-envelope protein induces sleep architecture changes in rats. Brain Res. 1994 Oct 3;659(1-2):254–258. doi: 10.1016/0006-8993(94)90888-5. [DOI] [PubMed] [Google Scholar]
  23. Raymon L. P., Kimes A. S., Tabakoff B., London E. D. SIDA et troubles du sommeil: effet du gp120 sur le métabolisme cérébral du glucose. C R Seances Soc Biol Fil. 1989;183(5):407–418. [PubMed] [Google Scholar]
  24. Slabaugh M. B., Roseman N. A. Retroviral protease-like gene in the vaccinia virus genome. Proc Natl Acad Sci U S A. 1989 Jun;86(11):4152–4155. doi: 10.1073/pnas.86.11.4152. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Sportsman J. R., Elder J. H. A microanalytical protein assay using laser densitometry. Anal Biochem. 1984 Jun;139(2):298–300. doi: 10.1016/0003-2697(84)90006-x. [DOI] [PubMed] [Google Scholar]
  26. Threadgill D. S., Steagall W. K., Flaherty M. T., Fuller F. J., Perry S. T., Rushlow K. E., Le Grice S. F., Payne S. L. Characterization of equine infectious anemia virus dUTPase: growth properties of a dUTPase-deficient mutant. J Virol. 1993 May;67(5):2592–2600. doi: 10.1128/jvi.67.5.2592-2600.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Tye B. K., Lehman I. R. Excision repair of uracil incorporated in DNA as a result of a defect in dUTPase. J Mol Biol. 1977 Dec 5;117(2):293–306. doi: 10.1016/0022-2836(77)90128-0. [DOI] [PubMed] [Google Scholar]
  28. Tye B. K., Nyman P. O., Lehman I. R., Hochhauser S., Weiss B. Transient accumulation of Okazaki fragments as a result of uracil incorporation into nascent DNA. Proc Natl Acad Sci U S A. 1977 Jan;74(1):154–157. doi: 10.1073/pnas.74.1.154. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Wagaman P. C., Hasselkus-Light C. S., Henson M., Lerner D. L., Phillips T. R., Elder J. H. Molecular cloning and characterization of deoxyuridine triphosphatase from feline immunodeficiency virus (FIV). Virology. 1993 Oct;196(2):451–457. doi: 10.1006/viro.1993.1501. [DOI] [PubMed] [Google Scholar]
  30. Walsh D. G., Horvath C. J., Hansen-Moosa A., MacKey J. J., Sehgal P. K., Daniel M. D., Desrosiers R. C., Ringler D. J. Cytokine influence on simian immunodeficiency virus replication within primary macrophages. TNF-alpha, but not GMCSF, enhances viral replication on a per-cell basis. Am J Pathol. 1991 Oct;139(4):877–887. [PMC free article] [PubMed] [Google Scholar]
  31. Williams M. V., Cheng Y. Human deoxyuridine triphosphate nucleotidohydrolase. Purification and characterization of the deoxyuridine triphosphate nucleotidohydrolase from acute lymphocytic leukemia. J Biol Chem. 1979 Apr 25;254(8):2897–2901. [PubMed] [Google Scholar]
  32. Zack J. A., Haislip A. M., Krogstad P., Chen I. S. Incompletely reverse-transcribed human immunodeficiency virus type 1 genomes in quiescent cells can function as intermediates in the retroviral life cycle. J Virol. 1992 Mar;66(3):1717–1725. doi: 10.1128/jvi.66.3.1717-1725.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES