Editing HIV (section)

====Replication and transcription====
[[File:Reverse Transcription.png|thumb|[[Reverse transcription]] of the HIV [[genome]] into [[double-stranded DNA]]]]

Shortly after the viral capsid enters the cell, an [[enzyme]] called [[reverse transcriptase]] liberates the positive-sense single-stranded [[RNA]] genome from the attached viral proteins and copies it into a [[cDNA|complementary DNA]] (cDNA) molecule.<ref name=Zheng>{{cite journal | vauthors = Zheng YH, Lovsin N, Peterlin BM | title = Newly identified host factors modulate HIV replication | journal = Immunology Letters | volume = 97 | issue = 2 | pages = 225–34 | year = 2005 | pmid = 15752562 | doi = 10.1016/j.imlet.2004.11.026 }}</ref> The process of reverse transcription is extremely error-prone, and the resulting mutations may cause [[Resistance to antiviral drugs|drug resistance]] or allow the virus to evade the body's immune system. The reverse transcriptase also has ribonuclease activity that degrades the viral RNA during the synthesis of cDNA, as well as DNA-dependent DNA polymerase activity that creates a [[Sense (molecular biology)|sense]] DNA from the ''antisense'' cDNA.<ref>{{cite web |url=http://student.ccbcmd.edu/courses/bio141/lecguide/unit3/viruses/hivlc.html |website=Doc Kaiser's Microbiology Home Page |title=IV. Viruses> F. Animal Virus Life Cycles > 3. The Life Cycle of HIV |publisher=Community College of Baltimore County |date=January 2008 |url-status=dead |archive-url=https://web.archive.org/web/20100726222939/http://student.ccbcmd.edu/courses/bio141/lecguide/unit3/viruses/hivlc.html |archive-date=July 26, 2010 |df=mdy-all }}</ref> Together, the cDNA and its complement form a double-stranded viral DNA that is then transported into the [[cell nucleus]]. The integration of the viral DNA into the host cell's [[genome]] is carried out by another viral enzyme called [[integrase]].<ref name=Zheng />

The integrated viral DNA may then lie dormant, in the latent stage of HIV infection.<ref name=Zheng /> To actively produce the virus, certain cellular [[transcription factor]]s need to be present, the most important of which is [[NF-κB|NF-''κ''B]] (nuclear factor kappa&nbsp;B), which is upregulated when T cells become activated.<ref name=Hiscott>{{cite journal | vauthors = Hiscott J, Kwon H, Génin P | title = Hostile takeovers: viral appropriation of the NF-kB pathway | journal = Journal of Clinical Investigation | volume = 107 | issue = 2 | pages = 143–151 | year = 2001 | pmid = 11160127 | pmc = 199181 | doi = 10.1172/JCI11918 }}</ref> This means that those cells most likely to be targeted, entered and subsequently killed by HIV are those actively fighting infection.

During viral replication, the integrated DNA [[provirus]] is [[Transcription (genetics)|transcribed]] into RNA. The full-length genomic RNAs (gRNA) can be packaged into new viral particles in a [[pseudodiploid]] form. The selectivity in the packaging is explained by the structural properties of the dimeric conformer of the gRNA. The gRNA dimer is characterized  by a tandem three-way junction within the gRNA monomer, in which the SD and AUG [[Stem-loop|hairpins]], responsible for splicing and translation respectively, are sequestered and the DIS (dimerization initiation signal) hairpin is exposed. The formation of the gRNA dimer is mediated by a 'kissing'  interaction between the DIS hairpin loops of the gRNA monomers. At the same time, certain guanosine residues in the gRNA are made available for binding of the nucleocapsid (NC) protein leading to the subsequent virion assembly.<ref>{{Cite journal|last1=Keane|first1=Sarah C.|last2=Heng|first2=Xiao|last3=Lu|first3=Kun|last4=Kharytonchyk|first4=Siarhei|last5=Ramakrishnan|first5=Venkateswaran|last6=Carter|first6=Gregory|last7=Barton|first7=Shawn|last8=Hosic|first8=Azra|last9=Florwick|first9=Alyssa|last10=Santos|first10=Justin|last11=Bolden|first11=Nicholas C.|date=2015-05-22|title=Structure of the HIV-1 RNA packaging signal|url=http://dx.doi.org/10.1126/science.aaa9266|journal=Science|volume=348|issue=6237|pages=917–921|doi=10.1126/science.aaa9266|pmid=25999508|pmc=4492308|bibcode=2015Sci...348..917K|issn=0036-8075}}</ref> The labile gRNA dimer has been also reported to achieve a more stable conformation following the NC binding, in which both the DIS and the U5:AUG regions of the gRNA participate in extensive base pairing.<ref>{{Cite journal|last1=Keane|first1=Sarah C.|last2=Van|first2=Verna|last3=Frank|first3=Heather M.|last4=Sciandra|first4=Carly A.|last5=McCowin|first5=Sayo|last6=Santos|first6=Justin|last7=Heng|first7=Xiao|last8=Summers|first8=Michael F.|date=2016-10-10|title=NMR detection of intermolecular interaction sites in the dimeric 5′-leader of the HIV-1 genome|journal=Proceedings of the National Academy of Sciences|volume=113|issue=46|pages=13033–13038|doi=10.1073/pnas.1614785113|pmid=27791166|pmc=5135362|bibcode=2016PNAS..11313033K |issn=0027-8424|doi-access=free}}</ref>

RNA can also be [[post-transcriptional modification|processed]] to produce mature [[messenger RNA]]s (mRNAs). In most cases, this processing involves [[RNA splicing]] to produce mRNAs that are shorter than the full-length genome. Which part of the RNA is removed during RNA splicing determines which of the HIV protein-coding sequences is translated.<ref name="Ocwieja">{{cite journal | vauthors = Ocwieja KE, Sherrill-Mix S, Mukherjee R, Custers-Allen R, David P, Brown M, Wang S, Link DR, Olson J, Travers K, Schadt E, Bushman FD | display-authors = 6 | title = Dynamic regulation of HIV-1 mRNA populations analyzed by single-molecule enrichment and long-read sequencing | journal = Nucleic Acids Research | volume = 40 | issue = 20 | pages = 10345–55 | date = November 2012 | pmid = 22923523 | pmc = 3488221 | doi = 10.1093/nar/gks753 | url = https://academic.oup.com/nar/article/40/20/10345/2414624 }}</ref>

Mature HIV mRNAs are exported from the nucleus into the [[cytoplasm]], where they are [[Translation (genetics)|translated]] to produce HIV proteins, including [[Rev (HIV)|Rev]]. As the newly produced Rev protein is produced it moves to the nucleus, where it binds to full-length, unspliced copies of virus RNAs and allows them to leave the nucleus.<ref name=Pollard>{{cite journal | vauthors = Pollard VW, Malim MH | title = The HIV-1 Rev protein | journal = Annual Review of Microbiology | volume = 52 | pages = 491–532 | year = 1998 | pmid = 9891806 | doi = 10.1146/annurev.micro.52.1.491 }}</ref> Some of these full-length RNAs function as mRNAs that are translated to produce the structural proteins Gag and Env. Gag proteins bind to copies of the virus RNA genome to package them into new virus particles.<ref>{{cite journal | vauthors = Butsch M, Boris-Lawrie K | title = Destiny of unspliced retroviral RNA: ribosome and/or virion? | journal = Journal of Virology | volume = 76 | issue = 7 | pages = 3089–94 | date = April 2002 | pmid = 11884533 | pmc = 136024 | doi = 10.1128/JVI.76.7.3089-3094.2002 }}</ref>
HIV-1 and HIV-2 appear to package their RNA differently.<ref>{{cite journal | vauthors = Hellmund C, Lever AM | title = Coordination of Genomic RNA Packaging with Viral Assembly in HIV-1 | journal = Viruses | volume = 8 | issue = 7 | pages = 192 | date = July 2016 | pmid = 27428992 | pmc = 4974527 | doi = 10.3390/v8070192 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Soto-Rifo R, Limousin T, Rubilar PS, Ricci EP, Décimo D, Moncorgé O, Trabaud MA, André P, Cimarelli A, Ohlmann T | display-authors = 6 | title = Different effects of the TAR structure on HIV-1 and HIV-2 genomic RNA translation | journal = Nucleic Acids Research | volume = 40 | issue = 6 | pages = 2653–67 | date = March 2012 | pmid = 22121214 | pmc = 3315320 | doi = 10.1093/nar/gkr1093 }}</ref> HIV-1 will bind to any appropriate RNA.<ref>{{Cite book|url=https://books.google.com/books?id=P3vQCgAAQBAJ&q=HIV-1+will+bind+to+any+appropriate+RNA&pg=PA51|title=Role of Lipids in Virus Assembly| vauthors = Saad JS, Muriaux DM |date=2015-07-28|publisher=Frontiers Media SA|isbn=978-2-88919-582-4|language=en}}</ref> HIV-2 will preferentially bind to the mRNA that was used to create the Gag protein itself.<ref>{{cite journal | vauthors = Ricci EP, Herbreteau CH, Decimo D, Schaupp A, Datta SA, Rein A, Darlix JL, Ohlmann T | display-authors = 6 | title = In vitro expression of the HIV-2 genomic RNA is controlled by three distinct internal ribosome entry segments that are regulated by the HIV protease and the Gag polyprotein | journal = RNA | volume = 14 | issue = 7 | pages = 1443–55 | date = July 2008 | pmid = 18495939 | pmc = 2441975 | doi = 10.1261/rna.813608 }}</ref>