Editing HIV (section)

===Structure and genome===
{{Main|Structure and genome of HIV}}
[[File:HI-virion-structure en.svg|thumb|upright=1.35|Diagram of the HIV virion]]
HIV is similar in structure to other retroviruses. It is roughly spherical<ref name=McGovern>{{cite journal | vauthors = McGovern SL, Caselli E, Grigorieff N, Shoichet BK | title = A common mechanism underlying promiscuous inhibitors from virtual and high-throughput screening | journal = Journal of Medicinal Chemistry | volume = 45 | issue = 8 | pages = 1712–22 | year = 2002 | pmid = 11931626 | doi = 10.1021/jm010533y | hdl = 11380/977912 }}</ref> with a diameter of about 120&nbsp;[[Nanometre|nm]], around 100,000&nbsp;times smaller in volume than a [[red blood cell]].<ref name=Microbiology3>Compared with overview in: {{cite book | vauthors = Fisher B, Harvey RP, Champe PC |title=Lippincott's Illustrated Reviews: Microbiology |publisher=Lippincott Williams & Wilkins |location=Hagerstown, MD |year=2007 |pages = 3 |isbn=978-0-7817-8215-9 }}</ref> It is composed of two copies of positive-[[Sense (molecular biology)|sense]] [[single-stranded]] [[RNA]] that codes for the virus' nine [[gene]]s enclosed by a conical [[capsid]] composed of 2,000 copies of the viral protein [[P24 capsid protein|p24]].<ref name=compendia>{{cite book | author = Various | year = 2008 | title = HIV Sequence Compendium 2008 Introduction | url = http://www.hiv.lanl.gov/content/sequence/HIV/COMPENDIUM/2008/frontmatter.pdf | access-date = March 31, 2009 }}</ref> The single-stranded RNA is tightly bound to nucleocapsid proteins, p7, and enzymes needed for the development of the virion such as [[reverse transcriptase]], [[protease]]s, [[ribonuclease]] and [[integrase]]. A matrix composed of the viral protein p17 surrounds the capsid ensuring the integrity of the virion particle.<ref name=compendia />

This is, in turn, surrounded by the [[viral envelope]], that is composed of the [[lipid bilayer]] taken from the membrane of a human host cell when the newly formed virus particle buds from the cell. The viral envelope contains proteins from the host cell and relatively few copies of the HIV envelope protein,<ref name=compendia /> which consists of a cap made of three molecules known as [[gp120|glycoprotein (gp) 120]], and a stem consisting of three [[gp41]] molecules that anchor the structure into the viral envelope.<ref name=Chan>{{cite journal | vauthors = Chan DC, Fass D, Berger JM, Kim PS | title = Core structure of gp41 from the HIV envelope glycoprotein | journal = Cell | volume = 89 | issue = 2 | pages = 263–73 | date = April 1997 | pmid = 9108481 | doi = 10.1016/S0092-8674(00)80205-6 | url = http://www.its.caltech.edu/~chanlab/PDFs/Chan_Cell_1997.pdf | s2cid = 4518241 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Klein JS, Bjorkman PJ | title = Few and far between: how HIV may be evading antibody avidity | journal = PLOS Pathogens | volume = 6 | issue = 5 | pages = e1000908 | date = May 2010 | pmid = 20523901 | pmc = 2877745 | doi = 10.1371/journal.ppat.1000908 | doi-access = free }}</ref> The envelope protein, encoded by the HIV [[Env (gene)|''env'']] gene, allows the virus to attach to target cells and fuse the viral envelope with the target [[cell membrane|cell's membrane]] releasing the viral contents into the cell and initiating the infectious cycle.<ref name=Chan />

[[File:Protein Structure Diagram of Fusion Peptide Epitope on HIV Spike (41863579304).jpg|thumb|A diagram of the HIV spike protein (green), with the fusion peptide epitope highlighted in red, and a broadly neutralizing antibody (yellow) binding to the fusion peptide]]
As the sole viral protein on the surface of the virus, the envelope protein is a major target for [[HIV vaccine]] efforts.<ref name="nih1998">{{cite press release | author=National Institute of Health | title=Crystal structure of key HIV protein reveals new prevention, treatment targets | date=June 17, 1998 |url=http://www3.niaid.nih.gov/news/newsreleases/1998/hivprotein.htm | access-date = September 14, 2006 |archive-url=https://web.archive.org/web/20060219112450/http://www3.niaid.nih.gov/news/newsreleases/1998/hivprotein.htm |archive-date=February 19, 2006}}</ref> Over half of the mass of the trimeric envelope spike is N-linked [[glycan]]s. The density is high as the glycans shield the underlying viral protein from neutralisation by antibodies. This is one of the most densely glycosylated molecules known and the density is sufficiently high to prevent the normal maturation process of glycans during biogenesis in the endoplasmic and Golgi apparatus.<ref>{{cite journal | vauthors = Behrens AJ, Vasiljevic S, Pritchard LK, Harvey DJ, Andev RS, Krumm SA, Struwe WB, Cupo A, Kumar A, Zitzmann N, Seabright GE, Kramer HB, Spencer DI, Royle L, Lee JH, Klasse PJ, Burton DR, Wilson IA, Ward AB, Sanders RW, Moore JP, Doores KJ, Crispin M | display-authors = 6 | title = Composition and Antigenic Effects of Individual Glycan Sites of a Trimeric HIV-1 Envelope Glycoprotein | journal = Cell Reports | volume = 14 | issue = 11 | pages = 2695–706 | date = March 2016 | pmid = 26972002 | pmc = 4805854 | doi = 10.1016/j.celrep.2016.02.058 }}</ref><ref>{{cite journal | vauthors = Pritchard LK, Spencer DI, Royle L, Bonomelli C, Seabright GE, Behrens AJ, Kulp DW, Menis S, Krumm SA, Dunlop DC, Crispin DJ, Bowden TA, Scanlan CN, Ward AB, Schief WR, Doores KJ, Crispin M | display-authors = 6 | title = Glycan clustering stabilizes the mannose patch of HIV-1 and preserves vulnerability to broadly neutralizing antibodies | journal = Nature Communications | volume = 6 | pages = 7479 | date = June 2015 | pmid = 26105115 | pmc = 4500839 | doi = 10.1038/ncomms8479 | bibcode = 2015NatCo...6.7479P }}</ref> The majority of the glycans are therefore stalled as immature 'high-mannose' glycans not normally present on human glycoproteins that are secreted or present on a cell surface.<ref>{{cite journal | vauthors = Pritchard LK, Harvey DJ, Bonomelli C, Crispin M, Doores KJ | title = Cell- and Protein-Directed Glycosylation of Native Cleaved HIV-1 Envelope | journal = Journal of Virology | volume = 89 | issue = 17 | pages = 8932–44 | date = September 2015 | pmid = 26085151 | pmc = 4524065 | doi = 10.1128/JVI.01190-15 }}</ref> The unusual processing and high density means that almost all broadly neutralising antibodies that have so far been identified (from a subset of patients that have been infected for many months to years) bind to, or are adapted to cope with, these envelope glycans.<ref>{{cite journal | vauthors = Crispin M, Doores KJ | title = Targeting host-derived glycans on enveloped viruses for antibody-based vaccine design | journal = Current Opinion in Virology | volume = 11 | pages = 63–9 | date = April 2015 | pmid = 25747313 | pmc = 4827424 | doi = 10.1016/j.coviro.2015.02.002 | author-link2 = Katie Doores }}</ref>

The molecular structure of the viral spike has now been determined by [[X-ray crystallography]]<ref>{{cite journal | vauthors = Julien JP, Cupo A, Sok D, Stanfield RL, Lyumkis D, Deller MC, Klasse PJ, Burton DR, Sanders RW, Moore JP, Ward AB, Wilson IA | display-authors = 6 | title = Crystal structure of a soluble cleaved HIV-1 envelope trimer | journal = Science | volume = 342 | issue = 6165 | pages = 1477–83 | date = December 2013 | pmid = 24179159 | pmc = 3886632 | doi = 10.1126/science.1245625 | bibcode = 2013Sci...342.1477J }}</ref> and [[cryogenic electron microscopy]].<ref>{{cite journal | vauthors = Lyumkis D, Julien JP, de Val N, Cupo A, Potter CS, Klasse PJ, Burton DR, Sanders RW, Moore JP, Carragher B, Wilson IA, Ward AB | display-authors = 6 | title = Cryo-EM structure of a fully glycosylated soluble cleaved HIV-1 envelope trimer | journal = Science | volume = 342 | issue = 6165 | pages = 1484–90 | date = December 2013 | pmid = 24179160 | pmc = 3954647 | doi = 10.1126/science.1245627 | bibcode = 2013Sci...342.1484L }}</ref> These advances in structural biology were made possible due to the development of stable [[Recombinant organism|recombinant]] forms of the viral spike by the introduction of an intersubunit [[disulphide bond]] and an [[isoleucine]] to [[proline]] [[mutation]] ([[radical replacement]] of an amino acid) in gp41.<ref>{{cite journal | vauthors = Sanders RW, Derking R, Cupo A, Julien JP, Yasmeen A, de Val N, Kim HJ, Blattner C, de la Peña AT, Korzun J, Golabek M, de Los Reyes K, Ketas TJ, van Gils MJ, King CR, Wilson IA, Ward AB, Klasse PJ, Moore JP | display-authors = 6 | title = A next-generation cleaved, soluble HIV-1 Env trimer, BG505 SOSIP.664 gp140, expresses multiple epitopes for broadly neutralizing but not non-neutralizing antibodies | journal = PLOS Pathogens | volume = 9 | issue = 9 | pages = e1003618 | date = September 2013 | pmid = 24068931 | pmc = 3777863 | doi = 10.1371/journal.ppat.1003618 | doi-access = free }}</ref> The so-called SOSIP [[Trimer (chemistry)|trimers]] not only reproduce the antigenic properties of the native viral spike, but also display the same degree of immature glycans as presented on the native virus.<ref>{{cite journal | vauthors = Pritchard LK, Vasiljevic S, Ozorowski G, Seabright GE, Cupo A, Ringe R, Kim HJ, Sanders RW, Doores KJ, Burton DR, Wilson IA, Ward AB, Moore JP, Crispin M | display-authors = 6 | title = Structural Constraints Determine the Glycosylation of HIV-1 Envelope Trimers | journal = Cell Reports | volume = 11 | issue = 10 | pages = 1604–13 | date = June 2015 | pmid = 26051934 | pmc = 4555872 | doi = 10.1016/j.celrep.2015.05.017 }}</ref> Recombinant trimeric viral spikes are promising vaccine candidates as they display less non-neutralising [[epitope]]s than recombinant monomeric gp120, which act to suppress the immune response to target epitopes.<ref>{{cite journal | vauthors = de Taeye SW, Ozorowski G, Torrents de la Peña A, Guttman M, Julien JP, van den Kerkhof TL, Burger JA, Pritchard LK, Pugach P, Yasmeen A, Crampton J, Hu J, Bontjer I, Torres JL, Arendt H, DeStefano J, Koff WC, Schuitemaker H, Eggink D, Berkhout B, Dean H, LaBranche C, Crotty S, Crispin M, Montefiori DC, Klasse PJ, Lee KK, Moore JP, Wilson IA, Ward AB, Sanders RW | display-authors = 6 | title = Immunogenicity of Stabilized HIV-1 Envelope Trimers with Reduced Exposure of Non-neutralizing Epitopes | journal = Cell | volume = 163 | issue = 7 | pages = 1702–15 | date = December 2015 | pmid = 26687358 | pmc = 4732737 | doi = 10.1016/j.cell.2015.11.056 }}</ref> 
[[File:HIV-genome.png|thumb|upright=2.05|Structure of the RNA genome of HIV-1]]
The RNA genome consists of at least seven structural landmarks ([[Long terminal repeat|LTR]], [[Trans-activation response element (TAR)|TAR]], [[HIV Rev response element|RRE]], PE, SLIP, CRS, and INS), and nine genes (''gag'', ''pol'', and ''env'', ''tat'', ''rev'', ''nef'', ''vif'', ''vpr'', ''vpu'', and sometimes a tenth ''tev'', which is a fusion of ''tat'', ''env'' and ''rev''), encoding 19 proteins. Three of these genes, ''gag'', ''pol'', and ''env'', contain information needed to make the structural proteins for new virus particles.<ref name=compendia /> For example, ''env'' codes for a protein called gp160 that is cut in two by a cellular protease to form gp120 and gp41. The six remaining genes, ''tat'', ''rev'', ''nef'', ''vif'', ''vpr'', and ''vpu'' (or ''vpx'' in the case of HIV-2), are regulatory genes for proteins that control the ability of HIV to infect cells, produce new copies of virus (replicate), or cause disease.<ref name=compendia />

The two ''[[Tat (HIV)|tat]]'' proteins (p16 and p14) are [[Activator (genetics)|transcriptional transactivators]] for the LTR [[Promoter (genetics)|promoter]] acting by binding the TAR RNA element. The TAR may also be processed into [[microRNA]]s that regulate the [[apoptosis]] genes ''[[ERCC1]]'' and ''[[IER3]]''.<ref name="pmid18299284">{{cite journal | vauthors = Ouellet DL, Plante I, Landry P, Barat C, Janelle ME, Flamand L, Tremblay MJ, Provost P | title = Identification of functional microRNAs released through asymmetrical processing of HIV-1 TAR element | journal = Nucleic Acids Research | volume = 36 | issue = 7 | pages = 2353–65 | date = April 2008 | pmid = 18299284 | pmc = 2367715 | doi = 10.1093/nar/gkn076 }}</ref><ref name="pmid19220914">{{cite journal | vauthors = Klase Z, Winograd R, Davis J, Carpio L, Hildreth R, Heydarian M, Fu S, McCaffrey T, Meiri E, Ayash-Rashkovsky M, Gilad S, Bentwich Z, Kashanchi F | title = HIV-1 TAR miRNA protects against apoptosis by altering cellular gene expression | journal = Retrovirology | volume = 6 | issue = 1 | pages =  18 | year = 2009 | pmid = 19220914 | pmc = 2654423 | doi = 10.1186/1742-4690-6-18 | doi-access = free }}</ref> The [[Rev (HIV)|''rev'']] protein (p19) is involved in shuttling RNAs from the nucleus and the cytoplasm by binding to the [[HIV Rev response element|RRE]] RNA element. The ''vif'' protein (p23) prevents the action of [[APOBEC3G]] (a cellular protein that [[Deamination|deaminates]] [[cytidine]] to [[uridine]] in the single-stranded viral DNA and/or interferes with reverse transcription<ref>{{cite journal | vauthors = Vasudevan AA, Smits SH, Höppner A, Häussinger D, Koenig BW, Münk C | title = Structural features of antiviral DNA cytidine deaminases | journal = [[Biological Chemistry (journal)|Biological Chemistry]] | volume = 394 | issue = 11 | pages = 1357–70 | date = Nov 2013 | pmid = 23787464 | doi = 10.1515/hsz-2013-0165 | s2cid = 4151961 | url = http://juser.fz-juelich.de/search?p=id:%22FZJ-2013-05757%22 | type = Submitted manuscript }}</ref>).  The ''[[vpr]]'' protein (p14) arrests [[cell division]] at [[G2/M checkpoint|G2/M]]. The ''nef'' protein (p27) down-regulates [[CD4]] (the major viral receptor), as well as the [[MHC class I]] and [[MHC class II|class II]] molecules.<ref name="pmid2014052">{{cite journal | vauthors = Garcia JV, Miller AD | title = Serine phosphorylation-independent downregulation of cell-surface CD4 by nef | journal = Nature | volume = 350 | issue = 6318 | pages = 508–11 | date = April 1991 | pmid = 2014052 | doi = 10.1038/350508a0 | bibcode = 1991Natur.350..508G | s2cid = 1628392 }}</ref><ref name="pmid8612235">{{cite journal | vauthors = Schwartz O, Maréchal V, Le Gall S, Lemonnier F, Heard JM | title = Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein | journal = Nature Medicine | volume = 2 | issue = 3 | pages = 338–42 | date = March 1996 | pmid = 8612235 | doi = 10.1038/nm0396-338 | s2cid = 7461342 }}</ref><ref name="pmid11593029">{{cite journal | vauthors = Stumptner-Cuvelette P, Morchoisne S, Dugast M, Le Gall S, Raposo G, Schwartz O, Benaroch P | title = HIV-1 Nef impairs MHC class II antigen presentation and surface expression | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 21 | pages = 12144–9 | date = October 2001 | pmid = 11593029 | pmc = 59782 | doi = 10.1073/pnas.221256498 | bibcode = 2001PNAS...9812144S | doi-access = free }}</ref>

''Nef'' also interacts with [[SH3 domain]]s. The ''vpu'' protein (p16) influences the release of new virus particles from infected cells.<ref name=compendia /> The ends of each strand of HIV RNA contain an RNA sequence called a [[long terminal repeat]] (LTR). Regions in the LTR act as switches to control production of new viruses and can be triggered by proteins from either HIV or the host cell. The [[Retroviral Psi packaging element|Psi element]] is involved in viral genome packaging and recognized by [[Group-specific antigen|''gag'']] and [[Rev (HIV)|''rev'']] proteins. The SLIP element ({{DNA sequence|TTTTTT}}) is involved in the [[Translational frameshift|frameshift]] in the ''gag''-''pol'' [[reading frame]] required to make functional ''pol''.<ref name=compendia />