HIV-1 integration occurs through a multistep process that includes two catalytic reactions: 3´endonucleolytic processing of proviral DNA ends (termed 3´processing) and integration of 3´-processed viral DNA into cellular DNA (referred to as strand transfer). In 3´processing IN binds to a short sequence located at either end of the long terminal repeat (LTR) of the viral DNA and catalyzes endonucleotide cleavage. This results in elimination of a dinucleotide from each of the 3´ends of the LTR. Cleaved DNA is then used as a substrate for integration or strand transfer. Strand transfer is a trans-esterification reaction involving a direct nucleophilic attack of the 3´hydroxy group of the two newly processed viral 3´-DNA ends on the phosphodiester backbone of the host target DNA. This leads to covalent insertion of viral DNA into the genome of the infected cell. Strand transfer occurs simultaneously at both ends of the viral DNA molecule, with an offset of precisely five base pairs between the two opposite points of insertion. The integration reaction is completed by removal of unpaired dinucleotides from the 5- ends of the viral DNA, repair of the single-stranded gaps created between the viral and target DNA molecules and ligation of 3-ends to 5-ends of the host DNA. Divalent metals, Mg or Mn, are required for 3-processing and strand transfer steps as well as for assembly of IN onto specific viral donor DNA to form a complex that is competent to carry out either function. Because the abundance of magnesium (Mg) versus manganese (Mn ) in human cells is 1,000,000-fold, magnesium seems a more readily available divalent cofactor for integration.