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J. Biol. Chem., Vol. 276, Issue 26, 23213-23216, June 29, 2001
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From the Laboratory of Molecular Biology, NIDDK, National
Institutes of Health, Bethesda, Maryland 20892
Retroviruses are a large and diverse family of
RNA viruses that synthesize a DNA copy of their RNA genome after
infection of the host cell. Integration of this viral DNA into host DNA is an essential step in the replication cycle of
HIV1 and other retroviruses
(reviewed in Refs. 1-3). The integrated viral DNA is transcribed to
make the RNA genome of progeny virions and the template for translation
of viral proteins. Following assembly, virions bud from the cell
surface and subsequently infect previously uninfected cells, thus
completing the replication cycle. An infecting retrovirus introduces a
large nucleoprotein complex into the cytoplasm of the host cell. This
complex, which is derived from the core of the infecting virion,
contains two copies of the viral RNA together with a number of viral
proteins, including reverse transcriptase and integrase. Reverse
transcription of the viral RNA occurs within the complex to make a
double-stranded DNA copy of the viral genome, the viral DNA substrate
for integration. The viral DNA remains associated with both viral and
cellular proteins in a nucleoprotein complex termed the preintegration complex. One constituent of the preintegration complex is the viral integrase protein, the key player in the integration of the viral
DNA into the host genome. The other components of the preintegration
complex that are transported to the nucleus along with the viral DNA
and integrase, and their possible functions, have not been firmly
established and are not discussed here. The critical DNA cutting and
joining events that integrate the viral DNA are carried out by the
integrase protein itself. Here we review our current knowledge of the
molecular mechanism of this reaction and discuss some of the key issues
that are yet to be understood.
Biochemical studies have elucidated the basic chemical mechanism
of integration, even though the organization of the active complex of
integrase with its DNA substrates remains to be determined. We will
focus on HIV integrase, but the key properties of this enzyme appear to
be shared among the entire retroviral integrase family. In the first
step of the integration process, two nucleotides are removed from each
3'-end of the viral DNA, a reaction termed 3'-end processing. Cleavage
occurs to the 3'-side of a CA dinucleotide that is conserved among
retroviruses, retrotransposons, and many DNA transposons, both in
prokaryotes and eukaryotes. This reaction exposes the terminal
3'-hydroxyl group that is to be joined to target DNA (Fig.
1B). In the second step, DNA
strand transfer, a pair of processed viral DNA ends is inserted into
the target DNA (Fig. 1C). In the case of HIV, the sites of
integration on the two target DNA strands are separated by 5 base
pairs. Repair of this integration intermediate (Fig. 1D)
results in a direct duplication of 5 base pairs flanking the integrated
viral DNA (not shown). The repair step requires removal of the two
unpaired nucleotides at the 5'-ends of the viral DNA, filling in the
single gaps, and finally ligation. Integrase is responsible for
3'-processing and DNA strand transfer, but the latter repair steps are
likely to be carried out by cellular enzymes (4, 5). There is little specificity for the sites of integration in host DNA, and insertion can
occur at essentially any location. The DNA cutting and joining steps of
3'-end processing and DNA strand transfer closely parallel the
reactions used by many transposons to move to new sites in the
genome.
The 3'-processing and DNA strand transfer reactions can be carried out
in vitro with purified integrase, a duplex oligonucleotide that mimics one end of the viral DNA, and a divalent metal ion. This
simplified in vitro system has proved to be invaluable for dissecting the biochemical mechanism of DNA integration. Stereochemical analysis of the reaction pathway has demonstrated that both
3'-processing and DNA strand transfer occur by a one-step
transesterification mechanism (6), the same result that was previously
obtained for the corresponding reactions mediated by the related Mu
transposase protein (7). In the 3'-processing reaction, water serves as the nucleophile for cleavage at the ends of the viral DNA. We may
envisage that DNA strand transfer occurs by a chemically similar mechanism, except that integrase positions the 3'-hydroxyl groups at
the ends of the viral DNA to simultaneously cleave the target DNA and
make covalent connections between the viral and target DNA. Although
3'-processing and DNA strand transfer are very similar reactions at the
chemical level, the way the active site region of integrase engages DNA
substrate must differ between processing and DNA strand transfer; for
the latter reaction the active sites must accommodate target DNA in
addition to the viral DNA ends.
HIV-1 integrase is comprised of three domains (Fig.
2) based on the susceptibility of the
linker regions to proteolysis (8), functional studies (8-10), and the
structures of the domains (Fig. 3), which
have been individually determined by x-ray crystallography or NMR.
MINIREVIEW
HIV Integrase, a Brief Overview from Chemistry to
Therapeutics*
INTRODUCTION
TOP
INTRODUCTION
The Mechanism of DNA...
Integrase
Unanswered Questions
Prospects for Developing...
REFERENCES
The Mechanism of DNA Integration
TOP
INTRODUCTION
The Mechanism of DNA...
Integrase
Unanswered Questions
Prospects for Developing...
REFERENCES
View larger version (13K):
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Fig. 1.
DNA cutting and joining steps in retroviral
integration. A, the viral DNA (orange) made
by reverse transcription is linear and blunt ended. B, in
the first step of the integration process, 3'-end processing, two
nucleotides are cleaved from each 3'-end of the viral DNA.
C, in the next step, DNA strand transfer, the hydroxyl
groups at the 3'-ends of the processed viral DNA attack a pair of
phosphodiester bonds in the target DNA (blue). The spacing
between the sites of attack on each target DNA strand is fixed and
characteristic for each retrovirus. D, the resulting
integration intermediate is redrawn to clarify the connections between
viral and target DNA. Integrase is responsible for both the
3'-processing and DNA strand transfer reactions that give rise to the
integration intermediate. Completion of DNA integration requires
removal of the two unpaired nucleotides at the 5'-ends of the viral
DNA, filling in the single strand gaps between host and viral DNA by a
DNA polymerase, and finally ligation. These steps are likely to be
carried out by cellular enzymes.
Integrase
TOP
INTRODUCTION
The Mechanism of DNA...
Integrase
Unanswered Questions
Prospects for Developing...
REFERENCES
View larger version (16K):
[in a new window]
Fig. 2.
Domain structure of retroviral
integrases. Integrase is composed of three domains. The core
domain contains the catalytic site. A triad of acidic residues, the
D,D-35-E motif, plays a key role in catalysis. This domain is well
conserved not only among retroviruses but also among many DNA
transposons in both prokaryotes and eukaryotes. The N-terminal domain
includes the conserved HHCC motif, which binds zinc. The C-terminal
domain is less well conserved.
View larger version (43K):
[in a new window]
Fig. 3.
Structures of the three domains of HIV-1
integrase shown as ribbon diagrams (48). A, the
catalytic core domain; B, the N-terminal domain;
C, the C-terminal domain. Protein Data Bank codes are 1BIS,
1WJC, and 1IHV, respectively.
The catalytic core domain contains the invariant triad of acidic residues, the D,D-35-E motif (8, 11-13), comprising residues Asp64, Asp116, and Glu152 in the case of HIV-1 integrase. Mutagenesis of these residues and their counterparts in related retroviral integrases abolishes or severely diminishes all catalytic activities in parallel (8, 11, 14, 15). By analogy with models of catalysis by DNA polymerases (16-18), it has been proposed that coordination of divalent metal ion to these residues plays a key role in catalysis (11). The structures of catalytic domain of HIV-1 integrase (19, 20) and the corresponding domain ASV integrase (21, 22) have been determined by x-ray crystallography. The catalytic residues Asp64, Asp116, and Glu152 of HIV-1 integrase and their counterparts in the ASV structures are in close proximity, coordinate divalent metal ion, and define the active site. However, the residues comprising the active site region exhibit considerable flexibility, suggesting that binding of DNA substrate is required to impose the precise configuration of residues that is required for catalysis. The structures of the HIV-1 and ASV integrase core domains are very similar to each other and to the catalytic domain of Mu transposase (23), reinforcing the parallelism of retroviral DNA integration and transposition. These structures revealed that retroviral integrases and their transposase cousins belong to a superfamily of polynucleotidyltransferases that share the same overall fold as Escherichia coli RNase H and have similar active sites (24, 25).
The HIV-1 catalytic domain is dimeric in solution (26) and in the crystal structures (Fig. 3A). The extensive surface area of the dimer interface suggests that it is biologically relevant. Yet, the spacing between the active sites in the nearly spherical dimer is not compatible with the spacing between the sites of insertion on the two strands of target DNA. The sites of insertion on each strand of target DNA are separated by 5 base pairs, corresponding to about 15 Å for helical B-form DNA. The functional unit of integrase should therefore have a pair of active sites separated by a similar spacing. However, in the crystal structures (Fig. 3A), the active sites in the dimer are separated by more than 30 Å measured as a straight line through the protein and by an even greater distance measured around the circumference of the dimer. Assuming that the dimer interface is maintained in the functional integrase multimer, at least a tetramer of integrase must be required for the complete integration reaction.
The N-terminal domain of HIV-1 integrase contains a conserved pair of
His and Cys residues, a motif similar to the zinc-coordinating residues
of zinc fingers. Although this domain does indeed bind zinc (27, 28),
its structure (Fig. 3B) (29) is totally different from that
of zinc fingers. It consists of a bundle of three 
-helices (Fig. 3C) (29, 30). It has an SH3 fold, although
there is no known functional relationship with the SH3 domains of other proteins.
Although the core domain of integrase is clearly responsible for
catalysis, the functional roles of the other two domains are less
clear. The C-terminal domain binds DNA nonspecifically. Because the
sites of integration into target DNA are relatively nonspecific, it has
been suggested that this domain may interact with target DNA. However,
experiments with chimeric integrases (31, 32) assign recognition of the
target site to the core domain, and cross-linking studies (33-36)
suggest that the C-terminal domain interacts with a subterminal region
just inside the very ends of the viral DNA end. The C-terminal domain
of retroviral integrases may therefore play a similar role to that of
the site-specific DNA binding domain of transposases, which also
recognize a subterminal sequence at the ends of the transposon DNA. The
function of the N-terminal domain of integrase is at present unknown.
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Unanswered Questions |
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TOP
INTRODUCTION
The Mechanism of DNA...
Integrase
Unanswered Questions
Prospects for Developing...
REFERENCES
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Although the structures of all three domains of integrase have been individually determined, their spatial arrangement in the active complex with DNA substrate is unknown. Three retroviral integrase structures of the core together with the C-terminal domain have been recently reported in the absence of bound DNA (37-39). The spatial relationship between the core and C-terminal domains is different in each of these structures indicating considerable flexibility in the linkage between the two domains. It is likely that binding of viral DNA substrate imposes the proper configuration of domains for the reaction to occur. Although integrase exists as monomers, dimers, and tetramers at high ionic strength, formation of large aggregates under reaction conditions has frustrated attempts to directly determine the organization of the active unit. Efforts to crystallize integrase together with DNA are further challenged by the nonspecific nature of the interaction between integrase and the viral DNA ends.
Many transposases, unlike their retroviral integrase counterparts, bind specifically to the transposon ends and form discrete nucleoprotein complexes that are amenable to direct structural and functional analysis. In the case of Mu transposase, the active unit of transposase is tetramer. Within the tetramer, only two of the four active sites directly participate in the DNA cleavage and joining reactions. A dimer of transposase carries out these reactions in the case of Tn5 (40) and Tn10.2 Thus, a dimer would seem to constitute the fundamental unit for this class of reactions, and the requirements for higher order multimers in some systems probably reflect differences in regulatory systems rather than a fundamental mechanism. The recent determination of the crystal structure of the Tn5 transposase dimer in complex with DNA substrate (40) provides a platform for modeling the interactions of DNA with the catalytic domain of integrase. Because the integrase catalytic domain is itself a dimer with an extensive interface, a similar architecture to that of the Tn5 complex would require a pair of dimers. Then, as in the case of Mu transposase, two of the active sites in the resulting tetramer would not directly participate in catalysis.
A puzzling phenomenon is the almost exclusive integration of a single
viral DNA substrate into one strand of the DNA target in reactions with
purified HIV integrase. In the cell and in vitro with
preintegration complexes, integration is coupled so that a pair of
viral DNA ends is integrated with a spacing of 5 base pairs separating
the sites of insertion on the two strands of target DNA. Although
inclusion of additional protein factors in the reaction has been
reported to stimulate coupled integration (41, 42), single-end
integration events still predominate. It appears that a yet to be
understood assembly pathway, and possibly additional factors, are
required to reconstitute the integration reaction with the full
fidelity observed with preintegration complexes in vitro and in
vivo. An alternative possibility is that aggregation of purified
integrase disfavors assembly of the correct complexes with two DNA ends
poised for integration; such aggregation may normally be prevented by
interaction with other components of the preintegration complex.
Indeed, it has been shown that improving the solubility of the closely
related Tn552 transposase greatly enhances the efficiency of double-end
versus single-end strand transfer (43). Perhaps the
strongest suggestion that additional host proteins may not be required
is the finding that disrupted HIV-1 virions, which contain few host
proteins, support efficient double-end strand transfer of exogenous
viral substrate DNA (44).
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Prospects for Developing Integrase Inhibitors as Therapeutic Antiviral Agents |
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INTRODUCTION
The Mechanism of DNA...
Integrase
Unanswered Questions
Prospects for Developing...
REFERENCES
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The development of effective inhibitors of HIV replication
targeted to reverse transcriptase and protease has demonstrated the
potential effectiveness of antiviral therapy for the treatment of AIDS.
Drugs targeted to integrase would be a valuable complement to reverse
transcriptase and protease inhibitors. However, no drugs have yet been
developed that act on integrase. The bottleneck has been the absence of
good lead compounds to serve as the starting point for drug
development. Although many compounds have been reported to inhibit
integrase, most of these lack selectivity and inhibit many other
enzymes as well. A concern has also been raised that because many
copies of integrase enter the cell with the infecting virus and only
two integrations are required, integrase might be an
intrinsically difficult enzyme to target. Recent identification of a
class of a compounds that unambiguously inhibits HIV replication in
cell culture by targeting integrase (45) counters this argument and
demonstrates the potential of integrase as an antiviral target. The
structure of a related inhibitor complexed with the active site of
integrase has also recently been determined (46). However, the much
higher affinity of these inhibitors for integrase in the presence of
viral DNA (47) and selectivity for the DNA strand transfer reaction
suggest that the binding modes in the absence and presence of DNA
substrate are not identical. It will likely be necessary to determine
the structure of these and other inhibitors in complex with an
integrase active site engaged with DNA to understand the interaction in
detail and provide a platform for drug design. Nevertheless, the
foundation of basic knowledge in understanding the mechanism of
retroviral integration promises to bear fruit in contributing to the
fight against AIDS.
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ACKNOWLEDGEMENTS |
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I thank Wei Yang for help with preparation of the ribbon diagrams and Wei Yang and Kenji Adzuma for comments on the manuscript.
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FOOTNOTES |
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* This minireview will be reprinted in the 2001 Minireview Compendium, which will be available in December, 2001.
To whom correspondence should be addressed: Bldg. 5, Rm. 301, 5 Center Dr. MSC 0560, NIDDK, National Institutes of Health, Bethesda, MD
20892-0560. Tel.: 301-496-4081; Fax: 301-496-0201; E-mail:
bobc@helix.nih.gov.
Published, JBC Papers in Press, May 9, 2001, DOI 10.1074/jbc.R100027200
2 D. Haniford, personal communication.
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ABBREVIATIONS |
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The abbreviations used are: HIV, human immunodeficiency virus; ASV, avian sarcoma virus.
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INTRODUCTION
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K. Busschots, J. Vercammen, S. Emiliani, R. Benarous, Y. Engelborghs, F. Christ, and Z. Debyser The Interaction of LEDGF/p75 with Integrase Is Lentivirus-specific and Promotes DNA Binding J. Biol. Chem., May 6, 2005; 280(18): 17841 - 17847. [Abstract] [Full Text] [PDF]
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A.él. Faure, C. Calmels, Céc. Desjobert, M. Castroviejo, A. Caumont-Sarcos, L. Tarrago-Litvak, S. Litvak, and V. Parissi HIV-1 integrase crosslinked oligomers are active in vitro Nucleic Acids Res., February 17, 2005; 33(3): 977 - 986. [Abstract] [Full Text] [PDF]
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A. T. Phan, V. Kuryavyi, J.-B. Ma, A. Faure, M.-L. Andreola, and D. J. Patel From The Cover: An interlocked dimeric parallel-stranded DNA quadruplex: A potent inhibitor of HIV-1 integrase PNAS, January 18, 2005; 102(3): 634 - 639. [Abstract] [Full Text] [PDF]
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P. Cherepanov, E. Devroe, P. A. Silver, and A. Engelman Identification of an Evolutionarily Conserved Domain in Human Lens Epithelium-derived Growth Factor/Transcriptional Co-activator p75 (LEDGF/p75) That Binds HIV-1 Integrase J. Biol. Chem., November 19, 2004; 279(47): 48883 - 48892. [Abstract] [Full Text] [PDF]
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 E. Deprez, S. Barbe, M. Kolaski, H. Leh, F. Zouhiri, C. Auclair, J.-C. Brochon, M. Le Bret, and J.-F. Mouscadet Mechanism of HIV-1 Integrase Inhibition by Styrylquinoline Derivatives in Vitro Mol. Pharmacol., January 1, 2004; 65(1): 85 - 98. [Abstract] [Full Text] [PDF]
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G. Maertens, P. Cherepanov, W. Pluymers, K. Busschots, E. De Clercq, Z. Debyser, and Y. Engelborghs LEDGF/p75 Is Essential for Nuclear and Chromosomal Targeting of HIV-1 Integrase in Human Cells J. Biol. Chem., August 29, 2003; 278(35): 33528 - 33539. [Abstract] [Full Text] [PDF]
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S. Priet, J.-M. Navarro, G. Querat, and J. Sire Reversion of the Lethal Phenotype of an HIV-1 Integrase Mutant Virus by Overexpression of the Same Integrase Mutant Protein J. Biol. Chem., May 30, 2003; 278(23): 20724 - 20730. [Abstract] [Full Text] [PDF]
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L. Zargarian, M. S. Benleumi, J.-G. Renisio, H. Merad, R. G. Maroun, F. Wieber, O. Mauffret, H. Porumb, F. Troalen, and S. Fermandjian Strategy to Discriminate between High and Low Affinity Bindings of Human Immunodeficiency Virus, Type 1 Integrase to Viral DNA J. Biol. Chem., May 23, 2003; 278(22): 19966 - 19973. [Abstract] [Full Text] [PDF]
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S. Sandmeyer Integration by design PNAS, May 13, 2003; 100(10): 5586 - 5588. [Full Text] [PDF]
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P. Cherepanov, G. Maertens, P. Proost, B. Devreese, J. Van Beeumen, Y. Engelborghs, E. De Clercq, and Z. Debyser HIV-1 Integrase Forms Stable Tetramers and Associates with LEDGF/p75 Protein in Human Cells J. Biol. Chem., January 3, 2003; 278(1): 372 - 381. [Abstract] [Full Text] [PDF]
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K. K. Bao, H. Wang, J. K. Miller, D. A. Erie, A. M. Skalka, and I. Wong Functional Oligomeric State of Avian Sarcoma Virus Integrase J. Biol. Chem., January 3, 2003; 278(2): 1323 - 1327. [Abstract] [Full Text] [PDF]
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Y. Suzuki and R. Craigie Regulatory Mechanisms by Which Barrier-to-Autointegration Factor Blocks Autointegration and Stimulates Intermolecular Integration of Moloney Murine Leukemia Virus Preintegration Complexes J. Virol., October 25, 2002; 76(23): 12376 - 12380. [Abstract] [Full Text] [PDF]
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 M. Dlakic A model of the replication fork blocking protein Fob1p based on the catalytic core domain of retroviral integrases Protein Sci., May 1, 2002; 11(5): 1274 - 1277. [Abstract] [Full Text] [PDF]
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K. K. Bao, A. M. Skalka, and I. Wong Presteady-state Analysis of Avian Sarcoma Virus Integrase. I. A SPLICING ACTIVITY AND STRUCTURE-FUNCTION IMPLICATIONS FOR COGNATE SITE RECOGNITION J. Biol. Chem., March 29, 2002; 277(14): 12089 - 12098. [Abstract] [Full Text] [PDF]
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S. Sinha, M. H. Pursley, and D. P. Grandgenett Efficient Concerted Integration by Recombinant Human Immunodeficiency Virus Type 1 Integrase without Cellular or Viral Cofactors J. Virol., March 7, 2002; 76(7): 3105 - 3113. [Abstract] [Full Text] [PDF]
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M. Melek, J. M. Jones, M. H. O'Dea, G. Pais, T. R. Burke Jr., Y. Pommier, N. Neamati, and M. Gellert Effect of HIV integrase inhibitors on the RAG1/2 recombinase PNAS, December 21, 2001; (2001) 12610699. [Abstract] [Full Text] [PDF]
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M. Melek, J. M. Jones, M. H. O'Dea, G. Pais, T. R. Burke Jr., Y. Pommier, N. Neamati, and M. Gellert Effect of HIV integrase inhibitors on the RAG1/2 recombinase PNAS, January 8, 2002; 99(1): 134 - 137. [Abstract] [Full Text] [PDF]
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