A mutation in integrase can compensate for mutations in the simian immunodeficiency virus att site

Zhenjian Du, Petr O. Ilyinskii, Kate Lally, Ronald Charles Desrosiers, Alan Engelman

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Sequences at the left terminus of U3 in the left long terminal repeat (LTR) and at the right terminus of U5 in the right LTR are important for integration of retroviral DNA. In the infectious pathogenic molecular clone of simian immunodeficiency virus strain mac239 (SIVmac239), 10 of the 12 terminal base pairs form an imperfect inverted repeat structure (5' TGGAAGGGATTT 3' [nucleotides 1 to 12] and 3' ACGATCCCTAAA 5' [nucleotides 10279 to 10268]). Nineteen different mutant forms of SIVmac239 proviral DNA with changes at one or more of the positions in each of the 12-terminal- base-pair regions were constructed. Viral replication was severely or completely compromised with nine of these mutants. Revertants appeared 40 to 50 days after transfection in two independent experiments with mutant 7, which contained changes of AGG to TAC at positions 5 to 7 in U3 and TCC to GAA at positions 10275 to 10273 in U5. Virus produced at these times from mutant 7 transfection replicated upon reinfection with only a slight delay when compared to the wild type. Sequence analysis of the LTR and integrase regions from infected cultures revealed two predominant changes: G to A at position 10275 in U5 and Glu to Lys at position 136 in integrase. Derivatives of clone 7 in which these changes were introduced individually and together were constructed by site-specific mutagenesis. Each change individually restored replication capacity only partially. However, the combination of both mutations restored replicative capacity to that of the original revertants. These results indicate that changes in integrase can compensate for mutations in the terminal nucleotides of the SIV LTR. The results further indicate that resistance to integrase inhibitors may include both integrase and LTR mutations.

Original languageEnglish (US)
Pages (from-to)8124-8132
Number of pages9
JournalJournal of Virology
Volume71
Issue number11
StatePublished - Nov 1997
Externally publishedYes

Fingerprint

Simian immunodeficiency virus
Integrases
Simian Immunodeficiency Virus
terminal repeat sequences
Terminal Repeat Sequences
mutation
Mutation
mutants
Nucleotides
nucleotides
transfection
Base Pairing
Transfection
Clone Cells
Integrase Inhibitors
clones
DNA
site-directed mutagenesis
virus replication
Site-Directed Mutagenesis

ASJC Scopus subject areas

  • Immunology

Cite this

A mutation in integrase can compensate for mutations in the simian immunodeficiency virus att site. / Du, Zhenjian; Ilyinskii, Petr O.; Lally, Kate; Desrosiers, Ronald Charles; Engelman, Alan.

In: Journal of Virology, Vol. 71, No. 11, 11.1997, p. 8124-8132.

Research output: Contribution to journalArticle

Du, Zhenjian ; Ilyinskii, Petr O. ; Lally, Kate ; Desrosiers, Ronald Charles ; Engelman, Alan. / A mutation in integrase can compensate for mutations in the simian immunodeficiency virus att site. In: Journal of Virology. 1997 ; Vol. 71, No. 11. pp. 8124-8132.
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