HIV-1 Integrase: Structural Organization, Conformational Changes, and Catalysis

Asante‐Appiah, Ernest; Skalka, Anna Marie

doi:10.1016/s0065-3527(08)60306-1

Cited by 202 publications

(182 citation statements)

References 67 publications

Supporting

Mentioning

181

Contrasting

Unclassified

Order By: Relevance

“…For in-depth reviews of these areas and other cellular factors implicated in the integration process, see refs. [8][9][10][31][32][33][111][112][113][114][115][116][117]. Ref.…”

Section: P75: Identification and Putative Cellular Function Of A Lentmentioning

confidence: 99%

Integrase, LEDGF/p75 and HIV replication

Poeschla

2008

Cell. Mol. Life Sci.

115

104

View full text Add to dashboard Cite

HIV integrates a DNA copy of its genome into a host cell chromosome in each replication cycle. The essential DNA cleaving and joining chemistry of integration is known, but there is less understanding of the process as it occurs in a cell, where two complex and dynamic macromolecular entities are joined: the viral pre-integration complex and chromatin. Among implicated cellular factors, much recent attention has coalesced around LEDGF/p75, a nuclear protein that may act as a chromatin docking factor or receptor for lentiviral pre-integration complexes. LEDGF/p75 tethers HIV integrase to chromatin, protects it from degradation, and strongly influences the genome-wide pattern of HIV integration. Depleting the protein from cells and/or over-expressing its integrase-binding domain blocks viral replication. Current goals are to establish the underlying mechanisms and to determine whether this knowledge can be exploited for antiviral therapy or for targeting lentiviral vector integration in human gene therapy.

show abstract

“…For in-depth reviews of these areas and other cellular factors implicated in the integration process, see refs. [8][9][10][31][32][33][111][112][113][114][115][116][117]. Ref.…”

Section: P75: Identification and Putative Cellular Function Of A Lentmentioning

confidence: 99%

Integrase, LEDGF/p75 and HIV replication

Poeschla

2008

Cell. Mol. Life Sci.

115

104

View full text Add to dashboard Cite

show abstract

“…HIV-1 IN is a 32-kDa protein that consists of three distinct structural domains (7): the N-terminal zinc-binding domain required for oligomerization (8 -10), the central catalytic core, and the less highly conserved C-terminal domain thought to be involved in DNA binding (11) and oligomerization of IN in vitro (12). The functional holoprotein required for concerted integration of two long terminal repeat ends is believed to exist as a homodimer of two tetramers (13,14).…”

Section: Human Immunodeficiency Virus (Hiv)mentioning

confidence: 99%

The Interaction of LEDGF/p75 with Integrase Is Lentivirus-specific and Promotes DNA Binding

Busschots

Vercammen

Emiliani

et al. 2005

Journal of Biological Chemistry

185

172

View full text Add to dashboard Cite

Human immunodeficiency virus (HIV)1 -1 belongs to the retroviridae that are characterized by reverse transcription of the diploid viral RNA genome into a double-stranded linear DNA molecule that is subsequently inserted into a host cell chromosome. Reverse transcription takes place in the cytoplasm of the infected cell and results in the formation of a compact and stable pre-integration complex (PIC) containing the viral reverse-transcribed genome and a number of virion-derived and cellular proteins. The family of the retroviridae can be broadly divided into simple and complex retroviridae, depending on their genomic composition and replication cycle. The retroviridae are then further subdivided into seven groups defined by evolutionary relatedness. Five of these groups represent retroviruses with oncogenic potential, and the other two groups are the lentiviruses and the spumaviruses (for a review, see Ref. 1). Lentiviridae (e.g. HIV-1, HIV-2, feline immunodeficiency virus (FIV), or simian immunodeficiency virus) are able to productively infect non-dividing cells, a feature that distinguishes them from oncoretroviridae (e.g. Moloney murine leukemia virus (Mo-MuLV), Rous sarcoma virus (RSV), and human T-cell lymphotropic virus (HTLV)-2), which require cell division for productive infection (2, 3). The viral integrase (IN) catalyzes the integration of the viral cDNA into the host genomic DNA, a process that is essential for replication and results in a provirus that will remain present as long as the cell survives (for reviews, see .HIV-1 IN is a 32-kDa protein that consists of three distinct structural domains (7): the N-terminal zinc-binding domain required for oligomerization (8 -10), the central catalytic core, and the less highly conserved C-terminal domain thought to be involved in DNA binding (11) and oligomerization of IN in vitro (12). The functional holoprotein required for concerted integration of two long terminal repeat ends is believed to exist as a homodimer of two tetramers (13,14). In cells stably overexpressing IN, the enzyme remains stably associated with condensed chromosomes during mitosis (15,16).The insight has grown that HIV relies on cellular proteins for completion of its replication cycle. Identification and characterization of these cellular cofactors will increase our understanding of the viral replication cycle and aid in the development of new antiviral drugs. Various cofactors of the lentiviral integration process have been proposed. Integrase interactor 1, a component of the SWI/SNF chromatin remodeling complex (17)(18)(19) DNA (16). Although the exact cellular function of LEDGF/ p75 is still unknown, it has been suggested to play a role in transcriptional regulation because it is isolated from HeLa cell extracts as an interactor of the transcriptional co-activator PC4 (25). LEDGF/p75 is a member of the hepatoma-derived growth factor family and has been proposed to play a protective role during stress-induced apoptosis (26 -28). DNA binding of LEDGF/p75, with specificity for stre...

show abstract

“…HIV integrase strand transfer inhibitors (STIs), which selectively target the strand transfer activity of integrase, possess potent anti-HIV activity in cell culture (11)(12)(13)(14), and the first one, raltegravir (15), has been approved for use in treatment experienced patients. Replication of HIV in the presence of increasing concentrations of STIs selects for resistant viruses, with amino acid changes within the integrase coding region (11,16).…”

Section: Hiv-1mentioning

confidence: 99%

Biochemical Analysis of HIV-1 Integrase Variants Resistant to Strand Transfer Inhibitors

Dicker

Terry

Lin

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

In this study, eight different HIV-1 integrase proteins containing mutations observed in strand transfer inhibitor-resistant viruses were expressed, purified, and used for detailed enzymatic analyses. All the variants examined were impaired for strand transfer activity compared with the wild type enzyme, with relative catalytic efficiencies (k p /K m ) ranging from 0.6 to 50% of wild type. The origin of the reduced strand transfer efficiencies of the variant enzymes was predominantly because of poorer catalytic turnover (k p ) values. However, smaller secondorder effects were caused by up to 4-fold increases in K m values for target DNA utilization in some of the variants. All the variants were less efficient than the wild type enzyme in assembling on the viral long terminal repeat, as each variant required more protein than wild type to attain maximal activity. In addition, the variant integrases displayed up to 8-fold reductions in their catalytic efficiencies for 3-processing. The Q148R variant was the most defective enzyme. The molecular basis for resistance of these enzymes was shown to be due to lower affinity binding of the strand transfer inhibitor to the integrase complex, a consequence of faster dissociation rates. In the case of the Q148R variant, the origin of reduced compound affinity lies in alterations to the active site that reduce the binding of a catalytically essential magnesium ion. Finally, except for T66I, variant viruses harboring the resistance-inducing substitutions were defective for viral integration.

show abstract

HIV-1 Integrase: Structural Organization, Conformational Changes, and Catalysis

Cited by 202 publications

References 67 publications

Integrase, LEDGF/p75 and HIV replication

Integrase, LEDGF/p75 and HIV replication

The Interaction of LEDGF/p75 with Integrase Is Lentivirus-specific and Promotes DNA Binding

Biochemical Analysis of HIV-1 Integrase Variants Resistant to Strand Transfer Inhibitors

Contact Info

Product

Resources

About