Editing Integrase (section)

== In HIV ==
[[File:The actual HIV integrase.jpg|thumb|left|alt=HIV catalytic core domain|Structural depiction of the HIV catalytic core domain based on the works of  Feng, L. and Kvaratskhelia, M. from the [https://www.rcsb.org/structure/4DMN protein database]]]

'''[[HIV]]''' '''integrase''' is a 32kDa viral protein consisting of three domains- [[N-terminus]], catalytic core domain, and C-terminus, which each have distinct properties and functions contributing to the efficacy of HIV integrase.<ref name=":0" />

The N-terminus is composed of 50 amino acid residues which contain a conserved histidine, histidine, cytosine, cytosine sequence which chelates zinc ions, furthermore enhancing the enzymatic activity of the catalytic core domain.<ref name=":0" /> As metal chelation is vital in integrase efficacy, it is a target for the development of retroviral therapies.<ref name=":0" />

The catalytic core domain, like the N-terminus, contains highly conserved amino acid residues -Asp64, Asp116, Glu152- as the conserved DDE (Asp-Asp-Glu) motif contributes to the endonuclease and polynucleotide transferase functions of integrase. Mutations in these regions inactivates integrase and prevents genome integration.<ref name=":0" />

The C-terminus domain binds to host DNA non-specifically and stabilizes the integration complex.<ref name=":0" />

=== Integration mechanism ===
Following synthesis of HIV's doubled stranded DNA genome, integrase binds to the long tandem repeats flanking the genome on both ends. Using its endonucleolytic activity, integrase cleaves a di or trinucleotide from both 3' ends of the genome in a processing known as 3'-processing.<ref name=":3">{{cite journal | vauthors = Mahboubi-Rabbani M, Abbasi M, Hajimahdi Z, Zarghi A | title = HIV-1 Reverse Transcriptase/Integrase Dual Inhibitors: A Review of Recent Advances and Structure-activity Relationship Studies | journal = Iranian Journal of Pharmaceutical Research | volume = 20 | issue = 2 | pages = 333–369 | date = 2021 | pmid = 34567166 | doi = 10.22037/ijpr.2021.115446.15370 | pmc = 8457747 }}</ref> The specificity of cleavage is improved through the use of cofactors such as Mn<sup>2+</sup> and Mg<sup>2+</sup> which interact with the DDE motif of the catalytic core domain, acting as cofactors to integrase function.<ref name=":3" />

The newly generated 3'OH groups disrupt the host DNA's [[phosphodiester linkage]]s through SN2-type nucleophilic attack.<ref name=":2" /> The 3' ends are covalently linked to the target DNA. The 5' over hangs of the viral genome are then cleaved using host repair enzymes, those same enzymes are believed to be responsible for the integration of the 5' end into the host genome forming the provirus.<ref name=":2" /><ref name=":3" />

=== Antiretroviral therapy ===
In November 2005, data from a [[Clinical trial|phase 2 study]] of an investigational HIV [[integrase inhibitor]], [[MK-0518]], demonstrated that the compound has potent antiviral activity. On October 12, 2007, the Food and Drug Administration (U.S.) approved the integrase inhibitor [[Raltegravir]] (MK-0518, brand name Isentress). The second integrase inhibitor, [[elvitegravir]], was approved in the U.S. in August 2012.