Natural selection results in conservation of HIV-1 integrase activity despite sequence variability

被引:16
作者
Reinke, R
Steffen, NR
Robinson, WE [1 ]
机构
[1] Univ Calif Irvine, Dept Pathol, Irvine, CA 92697 USA
[2] Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92697 USA
[3] Univ Calif Irvine, Dept Informat & Comp Sci, Irvine, CA 92697 USA
关键词
virus proteins; biochemistry; enzymology; virus evolution; natural selection; functional genomics; antiretroviral therapy;
D O I
10.1097/00002030-200105040-00002
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Background: Integration of the HIV genome by integrase is absolutely required for productive infection. Objective: To determine the role of natural selection on HIV integrase biology. Design: To study the activities of HIV integrases from a limited panel of North American clinical isolates from HIV-infected patients and to compare these proteins with integrases from two laboratory adapted reference strains (HIVIIIRF and HIVNL4-3) Methods: HIV was isolated and the particle-associated RNA was reverse transcribed and sequenced. Replication kinetics of molecularly cloned viruses containing each variant integrase were studied in tissue culture. The mutant integrase proteins were expressed, purified and specific activities of the enzymes were derived for both 3' end-processing and disintegration reactions. Results: Despite 3-5% variability in integrase at the amino acid level, viruses showed no statistically significant differences in growth kinetics compared with the reference HIVNL4-3 virus and only minor differences were observed in 3' end-processing and disintegration activities. All integrase proteins demonstrated similar sensitivity to an integrase inhibitor L-chicoric acid. Conclusions: These results demonstrate that integrase genes derived from HIV-infected individuals can differ from reference sequences but these mutations do not result in loss of function, including susceptibility to an integrase inhibitor; therefore, integrase remains an attractive target for antiviral drug design, as mutability appears to be restricted by function. (C) 2001 Lippincott Williams & Wilkins.
引用
收藏
页码:823 / 830
页数:8
相关论文
共 42 条
[1]   Molecular mechanisms in retrovirus DNA integration [J].
Asante-Appiah, E ;
Skalka, AM .
ANTIVIRAL RESEARCH, 1997, 36 (03) :139-156
[2]   Combinations of reverse transcriptase, protease, and integrase inhibitors can be synergistic in vitro against drug-sensitive and RT inhibitor-resistant molecular clones of HIV-1 [J].
Beale, KK ;
Robinson, EW .
ANTIVIRAL RESEARCH, 2000, 46 (03) :223-232
[3]   Variations in HIV-1 pol gene associated with reduced sensitivity to antiretroviral drugs in treatment-naive patients [J].
Birk, M ;
Sönnerborg, A .
AIDS, 1998, 12 (18) :2369-2375
[4]   DOMAINS OF THE INTEGRASE PROTEIN OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 RESPONSIBLE FOR POLYNUCLEOTIDYL TRANSFER AND ZINC-BINDING [J].
BUSHMAN, FD ;
ENGELMAN, A ;
PALMER, I ;
WINGFIELD, P ;
CRAIGIE, R .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (08) :3428-3432
[5]   Conserved sequences in the carboxyl terminus of integrase that are essential for human immunodeficiency virus type 1 replication [J].
Cannon, PM ;
Byles, ED ;
Kingsman, SM ;
Kingsman, AJ .
JOURNAL OF VIROLOGY, 1996, 70 (01) :651-657
[6]   HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 INTEGRASE - EFFECT ON VIRAL REPLICATION OF MUTATIONS AT HIGHLY CONSERVED RESIDUES [J].
CANNON, PM ;
WILSON, W ;
BYLES, E ;
KINGSMAN, SM ;
KINGSMAN, AJ .
JOURNAL OF VIROLOGY, 1994, 68 (08) :4768-4775
[7]   REVERSAL OF INTEGRATION AND DNA SPLICING MEDIATED BY INTEGRASE OF HUMAN-IMMUNODEFICIENCY-VIRUS [J].
CHOW, SA ;
VINCENT, KA ;
ELLISON, V ;
BROWN, PO .
SCIENCE, 1992, 255 (5045) :723-726
[8]   pol gene diversity of five human immunodeficiency virus type 1 subtypes: Evidence for naturally occurring mutations that contribute to drug resistance, limited recombination patterns, and common ancestry for subtypes B and D [J].
Cornelissen, M ;
vandenBurg, R ;
Zorgdrager, F ;
Lukashov, V ;
Goudsmit, J .
JOURNAL OF VIROLOGY, 1997, 71 (09) :6348-6358
[9]   THE DNA-BINDING DOMAIN OF HIV-1 INTEGRASE HAS AN SH3-LIKE FOLD [J].
EIJKELENBOOM, APAM ;
LUTZKE, RAP ;
BOELENS, R ;
PLASTERK, RHA ;
KAPTEIN, R ;
HARD, K .
NATURE STRUCTURAL BIOLOGY, 1995, 2 (09) :807-810
[10]   IDENTIFICATION OF DISCRETE FUNCTIONAL DOMAINS OF HIV-1 INTEGRASE AND THEIR ORGANIZATION WITHIN AN ACTIVE MULTIMERIC COMPLEX [J].
ENGELMAN, A ;
BUSHMAN, FD ;
CRAIGIE, R .
EMBO JOURNAL, 1993, 12 (08) :3269-3275