Editing HIV (section)

====Entry to the cell====
[[File:HIV Membrane fusion panel.svg|thumb|upright=1.8|'''Mechanism of viral entry''': '''1.''' Initial interaction between gp120 and CD4. '''2.''' Conformational change in gp120 allows for secondary interaction with CXCR4. '''3.''' The distal tips of gp41 are inserted into the cellular membrane. '''4.''' gp41 undergoes significant conformational change; folding in half and forming coiled-coils. This process pulls the viral and cellular membranes together, fusing them.]]

The HIV virion enters [[macrophage]]s and CD4<SUP>+</SUP> [[T cells]] by the [[adsorption]] of [[glycoprotein]]s on its surface to receptors on the target cell followed by fusion of the [[viral envelope]] with the target cell membrane and the release of the HIV capsid into the cell.<ref name=Chan2>{{cite journal | vauthors = Chan DC, Kim PS | title = HIV entry and its inhibition | journal = Cell | volume = 93 | issue = 5 | pages = 681–4 | year = 1998 | pmid = 9630213 | doi = 10.1016/S0092-8674(00)81430-0 | s2cid = 10544941 | doi-access = free }}</ref><ref name=Wyatt>{{cite journal | vauthors = Wyatt R, Sodroski J | title = The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens | journal = Science | volume = 280 | issue = 5371 | pages = 1884–8 | year = 1998 | pmid = 9632381 | doi = 10.1126/science.280.5371.1884 | bibcode = 1998Sci...280.1884W }}</ref>

Entry to the cell begins through interaction of the trimeric envelope complex ([[gp160]] spike) on the HIV viral envelope and both [[CD4]] and a chemokine co-receptor (generally either [[CCR5]] or [[CXCR4]], but others are known to interact) on the target cell surface.<ref name=Chan2 /><ref name=Wyatt /> Gp120 binds to [[integrin]] α<sub>4</sub>β<sub>7</sub> activating [[LFA-1]], the central integrin involved in the establishment of [[virological synapse]]s, which facilitate efficient cell-to-cell spreading of HIV-1.<ref name=Arthos>{{cite journal | vauthors = Arthos J, Cicala C, Martinelli E, Macleod K, Van Ryk D, Wei D, Xiao Z, Veenstra TD, Conrad TP, Lempicki RA, McLaughlin S, Pascuccio M, Gopaul R, McNally J, Cruz CC, Censoplano N, Chung E, Reitano KN, Kottilil S, Goode DJ, Fauci AS | title = HIV-1 envelope protein binds to and signals through integrin alpha(4)beta(7), the gut mucosal homing receptor for peripheral T cells | journal = Nature Immunology | volume = 9| issue = 3 | pages = 301–9 | year = 2008 | pmid = 18264102 | doi = 10.1038/ni1566 | s2cid = 205361178 }}</ref> The gp160 spike contains binding domains for both CD4 and chemokine receptors.<ref name=Chan2 /><ref name=Wyatt />

The first step in fusion involves the high-affinity attachment of the CD4 binding domains of [[gp120]] to CD4. Once gp120 is bound with the CD4 protein, the envelope complex undergoes a structural change, exposing the chemokine receptor binding domains of gp120 and allowing them to interact with the target chemokine receptor.<ref name=Chan2 /><ref name=Wyatt /> This allows for a more stable two-pronged attachment, which allows the [[N-terminus|N-terminal]] fusion peptide gp41 to penetrate the cell membrane.<ref name=Chan2 /><ref name=Wyatt /> [[Repeated sequence (DNA)|Repeat sequences]] in gp41, HR1, and HR2 then interact, causing the collapse of the extracellular portion of gp41 into a hairpin shape. This loop structure brings the virus and cell membranes close together, allowing fusion of the membranes and subsequent entry of the viral capsid.<ref name=Chan2 /><ref name=Wyatt />

After HIV has bound to the target cell, the HIV RNA and various enzymes, including reverse transcriptase, integrase, ribonuclease, and protease, are injected into the cell.<ref name=Chan2 />{{Failed verification|date=April 2014}} During the [[microtubule]]-based transport to the nucleus, the viral single-strand RNA genome is transcribed into double-strand DNA, which is then integrated into a host chromosome.

HIV can infect [[dendritic cell]]s (DCs) by this CD4-CCR5 route, but another route using [[Mannose receptor|mannose-specific C-type lectin receptors]] such as [[DC-SIGN]] can also be used.<ref name=Pope_2003>{{cite journal | vauthors = Pope M, Haase AT | title = Transmission, acute HIV-1 infection and the quest for strategies to prevent infection | journal = Nature Medicine | volume = 9 | issue = 7 | pages = 847–52 | year = 2003 | pmid = 12835704 | doi = 10.1038/nm0703-847 | s2cid = 26570505 | doi-access = free }}</ref> DCs are one of the first cells encountered by the virus during sexual transmission. They are currently thought to play an important role by transmitting HIV to T cells when the virus is captured in the [[mucosa]] by DCs.<ref name=Pope_2003 /> The presence of [[FEZ-1]], which occurs naturally in [[neuron]]s, is believed to prevent the infection of cells by HIV.<ref>{{cite journal | vauthors = Haedicke J, Brown C, Naghavi MH | title = The brain-specific factor FEZ1 is a determinant of neuronal susceptibility to HIV-1 infection | journal = Proceedings of the National Academy of Sciences | volume = 106 | issue = 33 | pages = 14040–14045 | date = Aug 2009 | pmid = 19667186 | pmc = 2729016 | doi = 10.1073/pnas.0900502106 | bibcode = 2009PNAS..10614040H | doi-access = free }}</ref>

[[File:Itrafig2.jpg|thumb|left|[[Clathrin-mediated endocytosis]]]]
HIV-1 entry, as well as entry of many other retroviruses, has long been believed to occur exclusively at the plasma membrane. More recently, however, productive infection by [[pH]]-independent, [[clathrin-mediated endocytosis]] of HIV-1 has also been reported and was recently suggested to constitute the only route of productive entry.<ref>{{cite journal | vauthors = Daecke J, Fackler OT, Dittmar MT, Kräusslich HG | title = Involvement of clathrin-mediated endocytosis in human immunodeficiency virus type 1 entry | journal = Journal of Virology | volume = 79 | issue = 3 | pages = 1581–1594 | date = 2005 | pmid = 15650184 | pmc = 544101 | doi = 10.1128/jvi.79.3.1581-1594.2005 }}</ref><ref>{{cite journal | vauthors = Miyauchi K, Kim Y, Latinovic O, Morozov V, Melikyan GB | title = HIV Enters Cells via Endocytosis and Dynamin-Dependent Fusion with Endosomes | journal = Cell | volume = 137 | issue = 3 | pages = 433–444 | date = 2009 | pmid = 19410541 | pmc = 2696170 | doi = 10.1016/j.cell.2009.02.046 }}</ref><ref>{{cite journal | vauthors = Koch P, Lampe M, Godinez WJ, Müller B, Rohr K, Kräusslich HG, Lehmann MJ | title = Visualizing fusion of pseudotyped HIV-1 particles in real time by live cell microscopy | journal = Retrovirology | volume = 6 | pages =  84 | date = 2009 | pmid = 19765276 | pmc = 2762461 | doi = 10.1186/1742-4690-6-84 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Thorley JA, McKeating JA, Rappoport JZ | title = Mechanisms of viral entry: sneaking in the front door | journal = Protoplasma | volume = 244 | issue = 1–4 | pages = 15–24 | date = 2010 | pmid = 20446005 | pmc = 3038234 | doi = 10.1007/s00709-010-0152-6 }}</ref><ref>{{cite journal | vauthors = Permanyer M, Ballana E, Esté JA | title = Endocytosis of HIV: anything goes | journal = Trends in Microbiology | volume = 18 | issue = 12 | pages = 543–551 | date = 2010 | pmid = 20965729 | doi = 10.1016/j.tim.2010.09.003 }}</ref>