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Review
. 2012 Jul;2(7):a006890.
doi: 10.1101/cshperspect.a006890.

HIV DNA integration

Robert Craigie  1 , Frederic D Bushman
Affiliations
Review

HIV DNA integration

Robert Craigie et al. Cold Spring Harb Perspect Med. 2012 Jul.

Abstract

Retroviruses are distinguished from other viruses by two characteristic steps in the viral replication cycle. The first is reverse transcription, which results in the production of a double-stranded DNA copy of the viral RNA genome, and the second is integration, which results in covalent attachment of the DNA copy to host cell DNA. The initial catalytic steps of the integration reaction are performed by the virus-encoded integrase (IN) protein. The chemistry of the IN-mediated DNA breaking and joining steps is well worked out, and structures of IN-DNA complexes have now clarified how the overall complex assembles. Methods developed during these studies were adapted for identification of IN inhibitors, which received FDA approval for use in patients in 2007. At the chromosomal level, HIV integration is strongly favored in active transcription units, which may promote efficient viral gene expression after integration. HIV IN binds to the cellular factor LEDGF/p75, which promotes efficient infection and tethers IN to favored target sites. The HIV integration machinery must also interact with many additional host factors during infection, including nuclear trafficking and pore proteins during nuclear entry, histones during initial target capture, and DNA repair proteins during completion of the DNA joining steps. Models for some of the molecular mechanisms involved have been proposed, but important details remain to be clarified.

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Figures

Figure 1.
Figure 1.
DNA breaking and joining reactions mediating DNA integration. DNA bases are shown by balls in the snap-together models, although the HIV DNA (10 kb) and the cellular chromosome (megabases) are not shown to scale. (A) The linear blunt-ended viral DNA (green and yellow) and target DNA (blue and red). (B) 3′ end processing. Two nucleotides are in most cases removed from each 3′ end of the viral DNA. (C) The 3′ ends generated by 3′ processing attack a pair of phosphodiester bonds in the target DNA. The sites of attack on the two target DNA strands are separated by five nucleotides in the case of HIV-1. The 3′ ends of the viral DNA are joined to the 5′ ends of the target DNA at the site of integration. The 5′ ends of the viral DNA are not joined to target DNA in the intermediate. (D) Completion of provirus formation requires removal of the two unpaired bases at the 5′ ends of the viral DNA, filling in the single-strand gaps between viral and target DNA and ligation of the 5′ ends of the viral DNA to target DNA. IN catalyzes the 3′ processing and DNA-strand transfer steps to form the integration intermediate. Subsequent steps are thought to be catalyzed by cellular enzymes. (E) The integrated provirus.
Figure 2.
Figure 2.
Structure of the complex of PFV IN and viral DNA (Hare et al. 2010). (A,B) Two views of the IN-DNA complex. (C) Top view of the complex, colored to emphasize that two monomers cross the center of symmetry and link up the two halves of the complex. (D) Stereo pair showing the structure of the active site, including two magnesium atoms bound to the three conserved acidic amino acids that comprise the active site.
Figure 3.
Figure 3.
Target DNA capture by the complex of PFV IN and viral DNA (Maertens et al. 2010). (A) Overview of the complex, showing target DNA in blue. (B,C) Two views of the DNA only, highlighting formation of the initial covalent link between the viral DNA 3′ ends and target DNA 5′ ends.
Figure 4.
Figure 4.
HIV integration site distributions on the human chromosomes (Wang et al. 2007). The human chromosomes are numbered at the sides of the diagram. HIV integration sites (20,000 total) are shown in green, gene density is shown in blue (measured as the count of RefSeq genes in a 500-kb interval), and the G/C content is shown in orange (measured in 500-kb intervals). The gray coloring indicates regions of centromeric repeats that have not been sequenced.
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