1887

Abstract

Two mutant virus strains in which the novel P225H mutation appeared in a V106A reverse transcriptase (RT)-mutated genetic background upon treatment of human immunodeficiency virus type 1 (HIV-1) with quinoxaline S-2720 were isolated. Surprisingly, the addition of the P225H mutation to the V106A RT mutant genetic background resensitized the V106A RT mutant virus to the nonnucleoside RT inhibitor (NNRTI) BHAP U-90152, but not to other NNRTIs. Construction of both recombinant viruses and recombinant RTs containing the V106A, P225H and V106A P225H mutations revealed that P225H was indeed responsible for the marked potentiation of the antiviral activity of BHAP against the P225H single-mutant virus and the V106A P225H double-mutant virus when compared to wild-type and V106A single-mutant viruses, respectively. An explanation for the markedly increased sensitivity of the P225H mutant HIV-1 RT to BHAP and not to the other NNRTIs was provided by the unique features of the X-ray structure of the RT-BHAP complex.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/0022-1317-79-6-1347
1998-06-01
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/jgv/79/6/9634074.html?itemId=/content/journal/jgv/10.1099/0022-1317-79-6-1347&mimeType=html&fmt=ahah

References

  1. Balzarini J., Naesens L., Slachmuylders J., Niphuis H., Rosenberg I., Holy A., Schellekens H., DeClercq E. 1991; 9-(2-Phos-phonylmethoxyethyl)adenine (PMEA) effectively inhibits retrovirus replication in vitro and simian immunodeficiency virus infection in rhesus monkeys. AIDS 5:21–28
    [Google Scholar]
  2. Balzarini J., Perez-Perez M. -J., San-Felix A., Camarasa M. -J., Bathurst I. C., Barr P. J., DeClercq E. 1992; Kinetics of inhibition of human immunodeficiency type 1 (HIV-1) reverse transcriptase by the novel HIV-1-specific nucleoside analogue [2´, 5´-bis-o(tert-butyl- dimethylsilyl)-²-D-ribofuranosyl]-3´-spiro-5”-(4”-amino-1”,2”-oxathiole- 2”,2”-dioxide)thymine (TSAO-T). Journal of Biological Chemistry 267:11831–11838
    [Google Scholar]
  3. D’Aquila R. T., Summers W. C. 1989; HIV-1 reverse transcriptase/ ribonuclease H: high level expression in Escherichia coli from a plasmid constructed using the polymerase chain reaction. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 2:579–587
    [Google Scholar]
  4. DeClercq E. 1994; HIV resistance to reverse transcriptase inhibitors. Biochemical Pharmacology 47:155–169
    [Google Scholar]
  5. De Clercq E. 1995a; Toward improved anti-HIV chemotherapy therapeutic strategies for intervention with HIV infections. Journal of Medicinal Chemistry 38:2491–2517
    [Google Scholar]
  6. DeClercq E. 1995b; Antiviral therapy for human immunodeficiency virus infections. Clinical Microbiology Reviews 8:200–239
    [Google Scholar]
  7. Dueweke T. J., Pushkarskaya T., Poppe S. M., Swaney S. M., Zhao J. Q., Chen I. S. Y., Stevenson M., Tarpley W. G. 1993; A mutation in reverse transcriptase of bis(heteroaryl)piperazine-resistant human immunodeficiency virus type 1 that confers increased sensitivity to other nonnucleoside inhibitors. Proceedings of the National Academy of Sciences USA 90:4713–4717
    [Google Scholar]
  8. Esnouf R. M. 1997; An extensively modified version of MolScript which includes greatly enhanced coloring capabilities. Journal ofMolecular Graphics 15:132–134
    [Google Scholar]
  9. Esnouf R. M., Ren J., Hopkins A. L., Ross C. K., Jones E. Y., Stammers D. K., Stuart D. I. 1997; Unique features in the structure of the complex between HIV-1 reverse transcriptase and the bis- (heteroaryl)piperazine U-90152 explain resistance mutations for this nonnucleoside inhibitor. Proceedings of the National Academy of Sciences USA 94:3984–3989
    [Google Scholar]
  10. Fletcher R. S., Holleschak G., Nagy E., Arion D., Borkow G., Gu Z., Wainberg M. A., Parniak M. A. 1996; Single -step purification of recombinant wild-type and mutant HIV-1 reverse transcriptase. Protein Expression and Purification 7:27–32
    [Google Scholar]
  11. Hizi A., Shaharabany M. 1992; Functional analysis of novel selective mutants of the reverse transcriptase of human immunodeficiency virus type 1. Journal of Biological Chemistry 267:18255–18258
    [Google Scholar]
  12. Hopkins A. L., Ren J., Esnouf R. M., Willcox B. E., Jones E. Y., Ross C, Miyasaka T., Walker R. T., Tanaka H., Stammers D. K., Stuart D. I. 1996; Compl exes of HIV-1 reverse transcriptase with inhibitors of the HEPT series reveal conformational changes relevant to the design of potent non-nucleoside inhibitors. Journal of Medicinal Chemistry 39:1589–1600
    [Google Scholar]
  13. Kellam P., Larder B. A. 1994; Recombinant virus assay: a rapid, phenotypic assay for assessment of drug susceptibility of human immunodeficiency virus type 1 isolates. Antimicrobial Agents and Chemotherapy 38:23–30
    [Google Scholar]
  14. Palaniappan C., Wisniewski M., Jacques P. S., LeGrice S. F. J., Fay P. J., Bambara R. A. 1997; Mutations within the primer grip region of HIV-1 reverse transcriptase result in loss of RNase H function. Journal of Biological Chemistry 272:11157–11164
    [Google Scholar]
  15. Pelemans H., Esnouf R., Dunkler A., Parniak M. A., Vandamme A. -M., Karlsson A., Kleim J. -P., DeClercq E., Balzarini J. 1997; Characteristics of the Pro225His mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase that appears under selective pressure of dose-escalating quinoxaline treatment of HIV-1. Journal of Virology 71:8195–8203
    [Google Scholar]
  16. Sambrook J., Fritsch E. F. 1989 Molecular Cloning :A Laboratory Manual, 2nd edn. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press;
    [Google Scholar]
  17. Schinazi R. F., Larder B. A., Mellors J. W. 1996; Mutations in HIV- 1 reverse transcriptase and protease associated with drug resistance. International Antiviral News 4:95–107
    [Google Scholar]
  18. Schmit J. -C., Cogniaux J., Hermans P., Van Vaeck C., Sprecher S., Van Remoortel B., Witvrouw M., Balzarini J., Desmyter J., De Clercq E., Vandamme A.-M. 1996A; Multiple drug resistance to nucleoside analogues and nonnucleoside reverse transcriptase inhibitorsin anefficiently replicating human immunodeficiency virus type 1 patient strain. Journal of Infectious Diseases 174:962–968
    [Google Scholar]
  19. Schmit J. -C., Ruiz L., Clotet B., Raventos A., Tor J., Leonard J., Desmyter J., DeClercq E., Vandamme A. -M. 1996b; Resistance- related mutations in the HIV-1 protease gene of patients treated for 1 year with the protease inhibitor ritonavir (ABT-538). AIDS 10:995–999
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/0022-1317-79-6-1347
Loading
/content/journal/jgv/10.1099/0022-1317-79-6-1347
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error