Izvorni kôd stranice CCR5

{{Infokutija gen}}
[[slika:HIV attachment.gif|thumb|right|310px| Veza [[HIV]]-a na CD4 + [[T-ćelija|T-pomoćnu ćeliju]]: <br>1 – gp120 virusni protein se veže za CD4. <br>2 – gp120 varijabilna petlja se pričvršćuje na koreceptor, bilo CCR5 ili CXCR4. <br>3 –  HIV ulazi u ćeliju.]] 
'''C-C hemokinski receptor tip 5''', znan i kao '''CCR5''' ili '''CD195''', je [[protein]] na površini  [[leukocit]]a, uključen [[imunski sistem]], kao [[receptor (biohemija)|receptor]] za [[hemokin]]e.<ref name="pmid31292161">{{cite journal | vauthors = Jiao X, Nawab O, Patel T, Kossenkov AV, Halama N, Jaeger D, Pestell RG| title = Recent Advances Targeting CCR5 for Cancer and Its Role in Immuno-Oncology | journal = Cancer Research | volume = 79 | issue = 19 | pages = 4801–4807 | date = Oct 2019 | pmid = 31292161 | pmc = 6810651 | doi = 10.1158/0008-5472.CAN-19-1167 }}</ref>

Kod ljudi, određene populacije naslijedile su mutaciju ''Delta 32'', što je rezultiralo [[delecija (genetika)|delecijom]]  dijela gena CCR5. [[Homozigot]] ni nositelji ove mutacije otporni su na [[HIV tropizam|M-tropske sojeve]] [[HIV|HIV-1 infekcije]].<ref name="pmid15556703">{{cite journal | vauthors = de Silva E, Stumpf MP | title = HIV and the CCR5-Delta32 resistance allele | journal = FEMS Microbiology Letters | volume = 241 | issue = 1 | pages = 1–12 | date = Dec 2004 | pmid = 15556703 | doi = 10.1016/j.femsle.2004.09.040 | doi-access = free }}</ref><ref name="pmid19213682">{{cite journal | vauthors = Hütter G, Nowak D, Mossner M, Ganepola S, Müssig A, Allers K, Schneider T, Hofmann J, Kücherer C, Blau O, Blau IW, Hofmann WK, Thiel E | title = Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation | journal = The New England Journal of Medicine | volume = 360 | issue = 7 | pages = 692–8 | date = Feb 2009 | pmid = 19213682 | doi = 10.1056/NEJMoa0802905 }}</ref><ref name="pmid21148083">{{cite journal | vauthors = Allers K, Hütter G, Hofmann J, Loddenkemper C, Rieger K, Thiel E, Schneider T | title = Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation | journal = Blood | volume = 117 | issue = 10 | pages = 2791–9 | date = Mar 2011 | pmid = 21148083 | doi = 10.1182/blood-2010-09-309591 | doi-access = free }}</ref><ref name="pmid24368413">{{cite journal | vauthors = Zhen A, Kitchen S | title = Stem-cell-based gene therapy for HIV infection | journal = Viruses | volume = 6 | issue = 1 | pages = 1–12 | date = Jan 2014 | pmid = 24368413 | pmc = 3917429 | doi = 10.3390/v6010001 }}</ref><ref name="pmid24597871">{{cite journal | vauthors = Kay MA, Walker BD | title = Engineering cellular resistance to HIV | journal = The New England Journal of Medicine | volume = 370 | issue = 10 | pages = 968–9 | date = Mar 2014 | pmid = 24597871 | doi = 10.1056/NEJMe1400593 }}</ref><ref name="pmid24597865">{{cite journal | vauthors = Tebas P, Stein D, Tang WW, Frank I, Wang SQ, Lee G, Spratt SK, Surosky RT, Giedlin MA, Nichol G, Holmes MC, Gregory PD, Ando DG, Kalos M, Collman RG, Binder-Scholl G, Plesa G, Hwang WT, Levine BL, June CH | display-authors = 6 | title = Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV | journal = The New England Journal of Medicine | volume = 370 | issue = 10 | pages = 901–10 | date = Mar 2014 | pmid = 24597865 | doi = 10.1056/NEJMoa1300662 | pmc=4084652}}</ref>

== Funkcija ==
Protein CCR5 pripada porodici [[beta hemokinski receptori|beta hemokinskih receptora]],  [[integralni membranski protein|integralnih membranskih proteina]].<ref name=Home>{{cite web | url = http://ghr.nlm.nih.gov/gene=ccr5 | title = CCR5 - chemokine (C-C motif) receptor 5 (gene/pseudogene) | work = Genetics Home Reference | access-date = 16. 3. 2021 | archive-date = 24. 9. 2009 | archive-url = https://web.archive.org/web/20090924213403/http://ghr.nlm.nih.gov/gene%3Dccr5 | url-status = dead }}</ref><ref name="pmid8639485">{{cite journal | vauthors = Samson M, Labbe O, Mollereau C, Vassart G, Parmentier M | title = Molecular cloning and functional expression of a new human CC-chemokine receptor gene | journal = Biochemistry | volume = 35 | issue = 11 | pages = 3362–7 | date = Mar 1996 | pmid = 8639485 | doi = 10.1021/bi952950g }}</ref> To je  [[G-protein spregnuti receptor]]<ref name=Home/> koji djeluje kao [[hemokinski receptor]] u [[CC hemokinski receptori|CC hemokinskoj grupi]].

CCR5-u  srodni [[ligand]]i uključuju [[CCL3]], [[CCL4]] (poznat i kao MIP 1''α'' i 1''β '') i [[CCL3L1]].<ref name=pmid11449371/><ref name="pmid11734558">{{cite journal | vauthors = Miyakawa T, Obaru K, Maeda K, Harada S, Mitsuya H | title = Identification of amino acid residues critical for LD78beta, a variant of human macrophage inflammatory protein-1alpha, binding to CCR5 and inhibition of R5 human immunodeficiency virus type 1 replication | journal = The Journal of Biological Chemistry | volume = 277 | issue = 7 | pages = 4649–55 | date = Feb 2002 | pmid = 11734558 | doi = 10.1074/jbc.M109198200 | doi-access = free }}</ref> CCR5 nadalje komunicira sa [[CCL5]] ([[hemotaksija|hemotaksijskim]] [[citokin]]skim proteinom,  poznatim i kao RANTES).<ref name="pmid11449371">{{cite journal | vauthors = Struyf S, Menten P, Lenaerts JP, Put W, D'Haese A, De Clercq E, Schols D, Proost P, Van Damme J | title = Diverging binding capacities of natural LD78beta isoforms of macrophage inflammatory protein-1alpha to the CC chemokine receptors 1, 3 and 5 affect their anti-HIV-1 activity and chemotactic potencies for neutrophils and eosinophils | journal = European Journal of Immunology | volume = 31 | issue = 7 | pages = 2170–8 | date = Jul 2001 | pmid = 11449371 | doi = 10.1002/1521-4141(200107)31:7<2170::AID-IMMU2170>3.0.CO;2-D | doi-access = free }}</ref><ref name="pmid14637022">{{cite journal | vauthors = Slimani H, Charnaux N, Mbemba E, Saffar L, Vassy R, Vita C, Gattegno L | title = Interaction of RANTES with syndecan-1 and syndecan-4 expressed by human primary macrophages | journal = Biochimica et Biophysica Acta (BBA) - Biomembranes | volume = 1617 | issue = 1–2 | pages = 80–8 | date = Oct 2003 | pmid = 14637022 | doi = 10.1016/j.bbamem.2003.09.006 }}</ref><ref name="pmid11116158">{{cite journal | vauthors = Proudfoot AE, Fritchley S, Borlat F, Shaw JP, Vilbois F, Zwahlen C, Trkola A, Marchant D, Clapham PR, Wells TN | title = The BBXB motif of RANTES is the principal site for heparin binding and controls receptor selectivity | journal = The Journal of Biological Chemistry | volume = 276 | issue = 14 | pages = 10620–6 | date = Apr 2001 | pmid = 11116158 | doi = 10.1074/jbc.M010867200 | doi-access = free }}</ref>

CCR5 je pretežno [[ekspresija gena|izražen]] na [[T-ćelija]]ma, [[makrofag]]ima, [[dendrit]]skim  ćelijama, [[eozinofili]]ima, [[glija|mikrogliji]] i subpopulacijama ćelija [[rak dojke|karcinoma dojke]] ili [[prostata|prostate]].<ref name="pmid22637726">{{cite journal | vauthors = Velasco-Velázquez M, Jiao X, De La Fuente M, Pestell TG, Ertel A, Lisanti MP, Pestell RG| title = CCR5 antagonist blocks metastasis of basal breast cancer cells | journal = Cancer Research | volume = 72 | issue = 15 | pages = 3839–50 | date = Aug 2012 | pmid = 22637726 | doi = 10.1158/0008-5472.CAN-11-3917 | doi-access = free }}</ref><ref name="pmid25452256">{{cite journal | vauthors = Sicoli D, Jiao X, Ju X, Velasco-Velazquez M, Ertel A, Addya S, Li Z, Andò S, Fatatis A, Paudyal B, Cristofanilli M, Thakur ML, Lisanti MP, Pestell RG| title = CCR5 receptor antagonists block metastasis to bone of v-Src oncogene-transformed metastatic prostate cancer cell lines | journal = Cancer Research | volume = 74 | issue = 23 | pages = 7103–14 | date = Dec 2014 | pmid = 25452256 | doi = 10.1158/0008-5472.CAN-14-0612 | pmc=4294544}}</ref> Ekspresija CCR5 selektivno se inducira tokom procesa transformacije raka i ne ispoljava se u normalnim [[epitel]]nim ćelijama dojke ili prostate. Otprilike 50% ljudskog karcinoma dojke ispoljilo je CCR5, prvenstveno kod trostruko negativnog karcinoma dojke.<ref name="pmid22637726"/>  CCR5 inhibitors blocked the migration and metastasis of breast and prostate cancer cells that expressed CCR5, suggesting that CCR5 may function as a new therapeutic target.<ref name="pmid22637726"/><ref name="pmid25452256"/><ref name="pmid25256399">{{cite journal | vauthors = Velasco-Velázquez M, Xolalpa W, Pestell RG | title = CCL5/CCR5 in breast cancer | journal = Expert Opin Ther Targets | volume = 18 | issue = 11 | pages = 1265–75 | date = Nov 2014 | pmid = 25256399 | doi = 10.1517/14728222.2014.949238}}</ref> Nedavna istraživanja sugeriraju da se CCR5 eksprimira u podgrupi ćelija karcinoma sa karakteristikama matičnih ćelija karcinoma, za koje je poznato da podstiču terapijsku rezistenciju, te da su inhibitori CCR5 povećali broj ćelija trenutno ubijenih [[hemoterapija|hemoterapijom]].<ref name="pmid29358169">{{cite journal | vauthors = Jiao X, Velasco-Velázquez MA, Wang M, Li Z, Rui H, Peck AR, Korkola JE, Chen X, Xu S, DuHadaway JB, Guerrero-Rodriguez S, Addya S, Sicoli D, Mu Z, Zhang G, Stucky A, Zhang X, Cristofanilli M, Fatatis A, Gray JW, Zhong JF, Prendergast GC, Pestell RG | title = CCR5 Governs DNA Damage Repair and Breast Cancer Stem Cell Expansion | journal = Cancer Res. | volume = 78 | issue = 7 | pages = 1657–71 | date = Apr 2018 | pmid = 29358169 | pmc = 6331183 | doi = 10.1158/0008-5472.CAN-17-0915 }}</ref> Vjerovatno je da CCR5 ima ulogu u upalnom odgovoru na infekciju, iako njegova tačna uloga u normalnoj imunskoj funkciji nije jasna. Regije ovog proteina su takođe ključne za vezanje hemokin-liganda, kao funkcionalni odgovor receptora i aktivnost koreceptora za HIV.<ref>{{cite journal | title=C-C chemokine receptor type five (CCR5): An emerging target for the control of HIV infection | journal=Applied & Translational Genomics | volume = 2 | issue = a | pages=3–16 | vauthors = Barmania F, Pepper MS | doi = 10.1016/j.atg.2013.05.004 | pmid=27942440 | pmc=5133339 | year=2013 }}</ref>

[[slika:CCR5 Primary Protein Sequence.png|thumb|Primarna proteinska sekvenca]]

== HIV ==
[[HIV|HIV-1]] najčešće koristi hemokinske receptore CCR5 i/ili [[CXCR4]] kao [[koreceptor]] za ulazak u ciljne imunske ćelije.<ref name="Murphy_2001">{{cite journal | vauthors = Murphy PM | title = Viral exploitation and subversion of the immune system through chemokine mimicry | journal = Nature Immunology | volume = 2 | issue = 2 | pages = 116–22 | date = Feb 2001 | pmid = 11175803 | doi = 10.1038/84214}}</ref> Ovi receptori nalaze se na površini imunskih ćelija domaćina, čime daju mogućnost ulaska [[virus]]a HIV-1 da zarazi ćeliju.<ref name="Alkhatib_2009">{{cite journal | vauthors = Alkhatib G | title = The biology of CCR5 and CXCR4 | journal = Current Opinion in HIV and AIDS  | volume = 4 | issue = 2 | pages = 96–103 | date = Mar 2009 | pmid = 19339947 | pmc = 2718543 | doi = 10.1097/COH.0b013e328324bbec }}</ref> The HIV-1 envelope glycoprotein structure is essential in enabling the viral entry of HIV-1 into a target host cell.<ref name="Alkhatib_2009" /> The envelope glycoprotein structure consists of two protein subunits cleaved from a Gp160 protein precursor encoded for by the HIV-1 ''env'' gene: the Gp120 external subunit and the Gp41 transmembrane subunit.<ref name="Alkhatib_2009" /> Ova [[glikoprotein]]ska struktura omotača raspoređena je u strukturu sličnu klasi koja se nalazi na površini viriona i sastoji se od trimera Gp120-Gp41 [[heterodimer]]a.<ref name="Alkhatib_2009" /> The Gp120 envelope protein is a chemokine mimic.  Iako mu nedostaje jedinstvena struktura kemokina, i dalje je sposoban da se veže za CCR5 i CXCR4 hemokinske receptore. Tokom HIV-1 infekcije, podjedinica glikoproteinskog omotača Gp120 veže se za glikoprotein CD4 i koreceptor za HIV-1, eksprimiran na ciljnoj ćeliji, formirajući heterotrimerni kompleks. Stvaranje ovog kompleksa stimulira oslobađanje fuzogenog peptida, zbog čega se virusna membrana spaja s membranom ciljanih ćelija domaćina. Budući da vezanje samo za CD4 ponekad može rezultirati oslobađanjem gp120, gp120 se mora dalje vezati za koreceptor CCR5 kako bi fuzija nastavila. Tirozin-sulfatni amino-kraj ovog ko-receptora je "bitna odrednica" vezanja za gp120 glikoprotein.<ref name="prn.org">{{cite web | url = http://www.prn.org/index.php/management/article/ccr5_inhibitors_hiv_86 | title = CCR5 Inhibitors and HIV }}</ref>  Koreceptor također prepoznaje V1-V2 regiju gp120 i premošćujući sloj (antiparalelni, 4-lančani β sloj koji povezuje unutrašnji i vanjki domen gp120). Drška V1-V2 može uticati na "upotrebu koreceptora putem peptidnog sastava, kao i stupnjem N-vezane glikozilacije". Međutim, za razliku od V1-V2, petlja V3 vrlo je varijabilna i stoga je najvažnija odrednica specifičnosti ko-receptora. Normalni [[ligand]]i za ovaj receptor, [[CCL5|RANTES]], [[CCL4|MIP-1β]] i [[CCL3|MIP-1α]], sposobni su suzbiti HIV-1 infekciju ''[[in vitro]]''. Kod osoba zaraženih HIV-om, virusi koji koriste CCR5 su pretežni tipovi izolirani tokom ranih stadija virusne infekcije,<ref>{{cite journal | vauthors = Anderson J, Akkina R | title = Complete knockdown of CCR5 by lentiviral vector-expressed siRNAs and protection of transgenic macrophages against HIV-1 infection | journal = Gene Therapy | volume = 14 | issue = 17 | pages = 1287–97 | date = Sep 2007 | pmid = 17597795 | doi = 10.1038/sj.gt.3302958 | doi-access = free }}</ref> što sugerira da ovi virusi mogu imati selektivnu prednost tokom prenosa ili akutne faze bolesti. Štaviše, najmanje polovina svih zaraženih osoba, u toku infekcije ima samo viruse koji koriste CCR5.

CCR5 je primarni ko-receptor koji gp120 koristi uzastopno sa CD4. Rezultat ovog vezanja je da se gp41, drugi proteinski proizvod gp160, oslobodi iz svoje metastabilne konformacije i ubaci u membranu ćelije domaćina. Iako nije potvrđeno, vezanje gp120-CCR5 uključuje dva ključna koraka: (1) tirozin-sulfatni amino kraj ovog koreceptora je "bitna odrednica" vezanja za gp120 i  (2) nakon koraka 1, mora postojati uzajamno djelovanje (sinergija, međusobna komunikacija) između gp120 i CCR5 transmembranskih domena.

CCR5 je neophodan za širenje R5-soja virusa HIV-1 .<ref name="Lieberman-Blum_2008">{{cite journal | vauthors = Lieberman-Blum SS, Fung HB, Bandres JC | title = Maraviroc: a CCR5-receptor antagonist for the treatment of HIV-1 infection | journal = Clinical Therapeutics | volume = 30 | issue = 7 | pages = 1228–50 | date = Jul 2008 | pmid = 18691983 | doi=10.1016/s0149-2918(08)80048-3}}</ref> Poznavanje mehanizma kojim ovaj soj HIV-1 posreduje infekciju podstaknulo je istraživanje u razvoju terapijskih intervencija za blokiranje funkcije CCR5.<ref>{{cite journal | vauthors = Nazari R, Joshi S | title = CCR5 as target for HIV-1 gene therapy | journal = Current Gene Therapy | volume = 8 | issue = 4 | pages = 264–72 | date = Aug 2008 | pmid = 18691022 | doi = 10.2174/156652308785160674 }}</ref> Brojni novi eksperimentalni HIV lijekovi, zvani [[CCR5 antagonist receptora]], dizajnirani su da ometaju vezanje između proteinskog omotača Gp120 i HIV koreceptora CCR5. Ovi eksperimentalni lijekovi uključuju [[PRO140]] ([[CytoDyn]]), [[Vicriviroc]] (ispitivanja faze III otkazana su u julu 2010.) ([[Schering plug]], [[Aplaviroc]] (GW-873140) ([[GlaxoSmithKline]]) i [[Maraviroc]] (UK-427857) ([[Pfizer]]).  FDA je odobrila za upotrebu Maraviroc u avgustu  2007. Za kliničku upotrebu, FDA ga je jedino do sada odobrila, čime je postao prvi inhibitor CCR5. Problem ovog pristupa je tšto, iako je CCR5 glavni koreceptor kojim HIV zaražava ćelije, nije jedini takav koreceptor. Moguće je da će se,  pod [[selekcijski pritisak|selekcijskim pritiskom]] HIV razviti u upotrebu drugog koreceptora. Međutim, ispitivanje virusne rezistencije na AD101, molekulski [[antagonist receptora|antagonista]] CCR5, pokazalo je da rezistentni virusi nisu prešli na drugi koreceptor (CXCR4), ali su ustrajali u upotrebi CCR5. Vezali su se za alternativne domene CCR5 ili na receptor sa većim afinitetom. Međutim, budući da još uvijek postoji još jedan koreceptor, vjerovatno je da nedostatak gena CCR5 ne čini imunost na virus. Virus također i dalje ima pristup CD4. Za razliku od CCR5, koji nije potreban (što dokazuju oni koji žive zdravim životom čak i kad im nedostaje gen kao rezultat mutacije delta32), CD4 je presudan u imunskom odbrambenom sistemu tijela.<ref name="urlUnderstanding Genetics">{{cite web | url = http://genetics.thetech.org/ask/ask336 | title = Understanding Genetics | publisher = The Tech Museum of Innovation, San Jose, CA | access-date = 16. 3. 2021 | archive-date = 17. 6. 2021 | archive-url = https://web.archive.org/web/20210617164823/https://genetics.thetech.org/ask/ask336 | url-status = dead }}</ref>  Čak i bez dostupnosti bilo koreceptora (čak i CCR5), virus i dalje može napasti ćelije, ako bi gp41 prošao kroz izmjenu (uključujući njegov [[citoplazma]]tski rep), što je rezultiralo neovisnošću CD4 bez potrebe CCR5 i/ili CXCR4 kao ulaznog puta.<ref name="pmid18353949">{{cite journal | vauthors = Taylor BM, Foulke JS, Flinko R, Heredia A, DeVico A, Reitz M | title = An alteration of human immunodeficiency virus gp41 leads to reduced CCR5 dependence and CD4 independence | journal = Journal of Virology | volume = 82 | issue = 11 | pages = 5460–71 | date = Jun 2008 | pmid = 18353949 | pmc = 2395218 | doi = 10.1128/JVI.01049-07 }}</ref>

== Kancer ==
Ekspresija CCR5 inducira se u [[epitel]]nim ćelijama dojke i prostate, nakon transformacije. Indukcija ekspresije CCR5 promovira ćelijsku invaziju, migraciju i [[metastaze]]. Indukcija metastaza pak uključuje usmjeravanje na metastatsko mjesto. Pokazalo se da CCR5 inhibitori, uključujući Maraviroc i Leronlimab, blokiraju metastazu na plućnim ćelijskim linijaama karcinoma dojke. U pretkliničkim ispitivanjima imunih miševa, CCR5 inhibitori blokirali su metastaze u kostima i mozgu.  CCR5 inhibitori također smanjuju infiltraciju makrofaga povezanih s tumorom.<ref name="pmid26238785">{{cite journal | vauthors = Frankenberger C, Rabe D, Bainer R, Sankarasharma D, Chada K, Krausz T, Gilad Y, Becker L, Rosner MR | title = Metastasis Suppressors Regulate the Tumor Microenvironment by Blocking Recruitment of Prometastatic Tumor-Associated Macrophages | journal = Cancer Res. | volume = 75 | issue = 19 | pages = 4063–73 | date = Oct 2015 | pmid = 26238785 | pmc = 4592465 | doi = 10.1158/0008-5472.CAN-14-3394}}</ref> Studija faze 1 kliničkog ispitivanja inhibitora CCR5 kod teško liječenih pacijenata sa metastatskim karcinomom debelog crijeva pokazala je objektivan klinički odgovor i smanjenje metastatskog opterećenja tumora.<ref name="pmid27070705">{{cite journal | vauthors = Halama N, Zoernig I, Berthel A, Kahlert C, Klupp F, Suarez-Carmona M, Suetterlin T, Brand K, Krauss J, Lasitschka F, Lerchl T, Luckner-Minden C, Ulrich A, Koch M, Weitz J, Schneider M, Buechler MW, Zitvogel L, Herrmann T, Benner A, Kunz C, Luecke S, Springfeld C, Grabe N, Falk CS, Jaeger D | title = Tumoral Immune Cell Exploitation in Colorectal Cancer Metastases Can Be Targeted Effectively by Anti-CCR5 Therapy in Cancer Patients | journal = Cancer Cell | volume = 29 | issue = 4 | pages = 587–601 | date = Apr 2016 | pmid = 27070705 | doi = 10.1016/j.ccell.2016.03.005| doi-access = free }}</ref>

== Mozak ==
Povećani nivoi CCR5 dio su upalnog odgovora na [[moždani udar]]. Blokiranje CCR5 lijekom Maraviroc (lijek odobren za HIV) može poboljšati oporavak nakon udara.<ref name="sciencemag-stroke">{{cite web | url = https://www.sciencemag.org/news/2019/02/hiv-drug-could-improve-recovery-after-stroke | title = HIV drug could improve recovery after stroke | website = ScienceMag| access-date = 22. 2. 2019| date = 21. 2. 2019 }}</ref><ref name="cell176i5">{{cite journal | vauthors = Joy MT, Assayag EB, Shabashov-Stone D, Liraz-Zaltsman S, Mazzitelli J, Arenas M, Abduljawad N, Kliper E, Korczyn AD, Thareja NS, Kesner EL, Zhou M, Huang S, Silva TK, Katz N, Bornstein NM, Silva AJ, Shohami E, Carmichael ST | title = CCR5 Is a Therapeutic Target for Recovery after Stroke and Traumatic Brain Injury | journal = Cell | volume = 176 | issue = 5 | pages = 1143–1157 | date = 21. 2. 2019 | pmid = 30794775| doi = 10.1016/j.cell.2019.01.044| pmc = 7259116 | doi-access = free }}</ref>

U  mozgu u razvoju, hemokini poput CCR5 utiču na migracije i veze [[neuron]]a. Nakon moždanog udara, čini se da smanjuju broj mjesta povezivanja na neuronima u blizini oštećenja.

== CCR5-Δ32 ==
CCR5-Δ32 (ili CCR5-D32 ili CCR5 delta 32) je [[alel]] CCR5-a.

== CCR5-Δ32 ==
CCR5-Δ32 (ili CCR5-D32 ili CCR5 delta 32) je [[alel]] CCR5-a.<ref name="Galvani_2003">{{cite journal | vauthors = Galvani AP, Slatkin M | title = Evaluating plague and smallpox as historical selective pressures for the CCR5-Delta 32 HIV-resistance allele | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 25 | pages = 15276–9 | date = Dec 2003 | pmid = 14645720 | pmc = 299980 | doi = 10.1073/pnas.2435085100 | bibcode = 2003PNAS..10015276G }}</ref><ref name="Stephens_1998">{{cite journal | vauthors = Stephens JC, Reich DE, Goldstein DB, Shin HD, Smith MW, Carrington M, Winkler C, Huttley GA, Allikmets R, Schriml L, Gerrard B, Malasky M, Ramos MD, Morlot S, Tzetis M, Oddoux C, di Giovine FS, Nasioulas G, Chandler D, Aseev M, Hanson M, Kalaydjieva L, Glavac D, Gasparini P, Kanavakis E, Claustres M, Kambouris M, Ostrer H, Duff G, Baranov V, Sibul H, Metspalu A, Goldman D, Martin N, Duffy D, Schmidtke J, Estivill X, O'Brien SJ, Dean M | display-authors = 6 | title = Dating the origin of the CCR5-Delta32 AIDS-resistance allele by the coalescence of haplotypes | journal = American Journal of Human Genetics | volume = 62 | issue = 6 | pages = 1507–15 | date = Jun 1998 | pmid = 9585595 | pmc = 1377146 | doi = 10.1086/301867 }}</ref>

CCR5 Δ32 je [[delecija (genetika)|delecija]] u paru od 32 baze, koja uvodi prerano [[stop kodon]] u CCR5 receptorski lokus, što rezultira nefunkcionalnim receptorom.<ref name="Dean_1996">{{cite journal | vauthors = Dean M, Carrington M, Winkler C, Huttley GA, Smith MW, Allikmets R, Goedert JJ, Buchbinder SP, Vittinghoff E, Gomperts E, Donfield S, Vlahov D, Kaslow R, Saah A, Rinaldo C, Detels R, O'Brien SJ | display-authors = 6 | title = Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study | journal = Science | volume = 273 | issue = 5283 | pages = 1856–62 | date = Sep 1996 | pmid = 8791590 | doi=10.1126/science.273.5283.1856| bibcode = 1996Sci...273.1856D| url = https://zenodo.org/record/1231080 }}</ref><ref name="Samson et al. 1996">{{cite journal | vauthors = Samson M, Libert F, Doranz BJ, Rucker J, Liesnard C, Farber CM, Saragosti S, Lapoumeroulie C, Cognaux J, Forceille C, Muyldermans G, Verhofstede C, Burtonboy G, Georges M, Imai T, Rana S, Yi Y, Smyth RJ, Collman RG, Doms RW, Vassart G, Parmentier M | title = Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene | journal = Nature | volume = 382 | issue = 6593 | pages = 722–5 | date = Aug 1996 | pmid = 8751444 | doi = 10.1038/382722a0 | bibcode = 1996Natur.382..722S }}</ref> CCR5 is required for M-tropic HIV-1 virus entry.<ref name = "Liu_1996">{{cite journal | vauthors = Liu R, Paxton WA, Choe S, Ceradini D, Martin SR, Horuk R, MacDonald ME, Stuhlmann H, Koup RA, Landau NR | title = Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection | journal = Cell | volume = 86 | issue = 3 | pages = 367–77 | date = Aug 1996 | pmid = 8756719 | doi =  10.1016/s0092-8674(00)80110-5}}</ref> [[Homozigot]]ne osobe (označeno sa Δ32 / Δ32) za CCR5 Δ32 ne ispoljavaju funkcionalne CCR5 receptore na  ćelijskim površinama i otporni su na infekciju [[HIV-1]]-om, uprkos višestrukoj izloženosti visokom riziku. [[Heterozigot]]ne (+ / Δ32) za mutantni [[alel]] imaju više od 50% smanjenje funkcionalnih CCR5 receptora na  površinama ćelija, zbog dimerizacije između mutiranih i divljih receptora, koji ometaju transportom CCR5 na površinu ćelije.<ref name="pmid9388191">{{cite journal | vauthors = Benkirane M, Jin DY, Chun RF, Koup RA, Jeang KT | title = Mechanism of transdominant inhibition of CCR5-mediated HIV-1 infection by ccr5delta32 | journal = The Journal of Biological Chemistry | volume = 272 | issue = 49 | pages = 30603–6 | date = Dec 1997 | pmid = 9388191 | doi =  10.1074/jbc.272.49.30603| doi-access = free }}</ref> Heterozygote carriers are resistant to HIV-1 infection relative to wild types and when infected, heterozygotes exhibit reduced [[viral load]]s and a 2-3-year-slower progression to [[AIDS]] relative to wild types.<ref name="Dean_1996"/><ref name = "Liu_1996"/><ref name="Michael_1997">{{cite journal | vauthors = Michael NL, Louie LG, Rohrbaugh AL, Schultz KA, Dayhoff DE, Wang CE, Sheppard HW | title = The role of CCR5 and CCR2 polymorphisms in HIV-1 transmission and disease progression | journal = Nature Medicine | volume = 3 | issue = 10 | pages = 1160–2 | date = Oct 1997 | pmid = 9334732 | doi =  10.1038/nm1097-1160 }}</ref> Heterozigoznost za ovaj mutirani alel također je pokazala da poboljšava odgovor na virus,  na antiretrovirusni tretman.<ref>{{cite journal | vauthors = Laurichesse JJ, Persoz A, Theodorou I, Rouzioux C, Delfraissy JF, Meyer L | title = Improved virological response to highly active antiretroviral therapy in HIV-1-infected patients carrying the CCR5 Delta32 deletion | journal = HIV Medicine | volume = 8 | issue = 4 | pages = 213–9 | date = maj 2007 | pmid = 17461848 | doi = 10.1111/j.1468-1293.2007.00455.x | doi-access = free }}</ref> U Evropi, CCR5 Δ32 ima učestalost alela ([[heterozigot]]a) od 10%, a frekvenciju homozigota od 1%.

Nedavna istraživanja pokazuju da CCR5 Δ32 poboljšava kogniciju i pamćenje. U 2016. istraživanja su pokazala da je uklanjanje gena CCR5 miševa značajno poboljšalo njihovo pamćenje.<ref name="techreview-ccr5">{{cite web | url = https://www.technologyreview.com/s/612997/the-crispr-twins-had-their-brains-altered/ | title = China's CRISPR twins might have had their brains inadvertently enhanced | website = Technology Review| access-date = 22. 2. 2019}}</ref>  CCR5 is a powerful suppressor for neuronal plasticity, learning, and memory; CCR5 over-activation by viral proteins may contribute to HIV-associated cognitive deficits.<ref name="PMC5213777">{{cite journal | vauthors = Zhou M, Greenhill S, Huang S, Silva TK, Sano Y, Wu S, Cai Y, Nagaoka Y, Sehgal M, Cai DJ, Lee YS, Fox K, Silva AJ | title = CCR5 is a suppressor for cortical plasticity and hippocampal learning and memory | journal = eLife | volume = 5 | date = 20. 12. 2016 | pmid = 27996938| pmc = 5213777 | doi = 10.7554/eLife.20985}}</ref>

== Također pogledajte==
* [[HIV tropizam]]
* [[HIV]]

== Reference ==
{{Reflist}}

== Dopunska literatura ==
{{refbegin|32em}}
* {{cite journal | vauthors = Wilkinson D | title = Cofactors provide the entry keys. HIV-1 | journal = Current Biology | volume = 6 | issue = 9 | pages = 1051–3 | date = Sep 1996 | pmid = 8805353 | doi = 10.1016/S0960-9822(02)70661-1}}
* {{cite journal | vauthors = Broder CC, Dimitrov DS | title = HIV and the 7-transmembrane domain receptors | journal = Pathobiology | volume = 64 | issue = 4 | pages = 171–9 | year = 1996 | pmid = 9031325 | doi = 10.1159/000164032 | url = https://zenodo.org/record/1235430 }}
* {{cite journal | vauthors = Choe H, Martin KA, Farzan M, Sodroski J, Gerard NP, Gerard C | title = Structural interactions between chemokine receptors, gp120 Env and CD4 | journal = Seminars in Immunology | volume = 10 | issue = 3 | pages = 249–57 | date = Jun 1998 | pmid = 9653051 | doi = 10.1006/smim.1998.0127 }}
* {{cite journal | vauthors = Sheppard HW, Celum C, Michael NL, O'Brien S, Dean M, Carrington M, Dondero D, Buchbinder SP | title = HIV-1 infection in individuals with the CCR5-Delta32/Delta32 genotype: acquisition of syncytium-inducing virus at seroconversion | journal = Journal of Acquired Immune Deficiency Syndromes | volume = 29 | issue = 3 | pages = 307–13 | date = Mar 2002 | pmid = 11873082 | doi = 10.1097/00042560-200203010-00013 }}
* {{cite journal | vauthors = Freedman BD, Liu QH, Del Corno M, Collman RG | title = HIV-1 gp120 chemokine receptor-mediated signaling in human macrophages | journal = Immunologic Research | volume = 27 | issue = 2–3 | pages = 261–76 | year = 2003 | pmid = 12857973 | doi = 10.1385/IR:27:2-3:261}}
* {{cite journal | vauthors = Esté JA | title = Virus entry as a target for anti-HIV intervention | journal = Current Medicinal Chemistry | volume = 10 | issue = 17 | pages = 1617–32 | date = Sep 2003 | pmid = 12871111 | doi = 10.2174/0929867033457098 }}
* {{cite journal | vauthors = Gallo SA, Finnegan CM, Viard M, Raviv Y, Dimitrov A, Rawat SS, Puri A, Durell S, Blumenthal R | title = The HIV Env-mediated fusion reaction | journal = Biochimica et Biophysica Acta (BBA) - Biomembranes | volume = 1614 | issue = 1 | pages = 36–50 | date = Jul 2003 | pmid = 12873764 | doi = 10.1016/S0005-2736(03)00161-5 }}
* {{cite journal | vauthors = Zaitseva M, Peden K, Golding H | title = HIV coreceptors: role of structure, posttranslational modifications, and internalization in viral-cell fusion and as targets for entry inhibitors | journal = Biochimica et Biophysica Acta (BBA) - Biomembranes | volume = 1614 | issue = 1 | pages = 51–61 | date = Jul 2003 | pmid = 12873765 | doi = 10.1016/S0005-2736(03)00162-7 }}
* {{cite journal | vauthors = Lee C, Liu QH, Tomkowicz B, Yi Y, Freedman BD, Collman RG | title = Macrophage activation through CCR5- and CXCR4-mediated gp120-elicited signaling pathways | journal = Journal of Leukocyte Biology | volume = 74 | issue = 5 | pages = 676–82 | date = Nov 2003 | pmid = 12960231 | doi = 10.1189/jlb.0503206 | doi-access = free }}
* {{cite journal | vauthors = Yi Y, Lee C, Liu QH, Freedman BD, Collman RG | title = Chemokine receptor utilization and macrophage signaling by human immunodeficiency virus type 1 gp120: Implications for neuropathogenesis | journal = Journal of Neurovirology | volume = 10 | issue =Suppl 1   | pages = 91–6 | year = 2004 | pmid = 14982745 | doi = 10.1080/753312758}}
* {{cite journal | vauthors = Seibert C, Sakmar TP | title = Small-molecule antagonists of CCR5 and CXCR4: a promising new class of anti-HIV-1 drugs | journal = Current Pharmaceutical Design | volume = 10 | issue = 17 | pages = 2041–62 | year = 2004 | pmid = 15279544 | doi = 10.2174/1381612043384312 }}
* {{cite journal | vauthors = Cutler CW, Jotwani R | title = Oral mucosal expression of HIV-1 receptors, co-receptors, and alpha-defensins: tableau of resistance or susceptibility to HIV infection? | journal = Advances in Dental Research | volume = 19 | issue = 1 | pages = 49–51 | year = 2006 | pmid = 16672549 | pmc = 3750741 | doi = 10.1177/154407370601900110 }}
* {{cite journal | vauthors = Ajuebor MN, Carey JA, Swain MG | title = CCR5 in T cell-mediated liver diseases: what's going on? | journal = Journal of Immunology | volume = 177 | issue = 4 | pages = 2039–45 | date = Aug 2006 | pmid = 16887960 | doi = 10.4049/jimmunol.177.4.2039 | doi-access = free }}
* {{cite journal | vauthors = Lipp M, Müller G | title = Shaping up adaptive immunity: the impact of CCR7 and CXCR5 on lymphocyte trafficking | journal = Verhandlungen der Deutschen Gesellschaft für Pathologie | volume = 87 | pages = 90–101 | year = 2003 | pmid = 16888899 }}
* {{cite journal | vauthors = Balistreri CR, Caruso C, Grimaldi MP, Listì F, Vasto S, Orlando V, Campagna AM, Lio D, Candore G | title = CCR5 receptor: biologic and genetic implications in age-related diseases | journal = Annals of the New York Academy of Sciences | volume = 1100 | issue =  1| pages = 162–72 | date = Apr 2007 | pmid = 17460174 | doi = 10.1196/annals.1395.014 | bibcode = 2007NYASA1100..162B}}
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* {{cite journal | vauthors = Uetsuki T, Naito A, Nagata S, Kaziro Y | title = Isolation and characterization of the human chromosomal gene for polypeptide chain elongation factor-1 alpha | journal = The Journal of Biological Chemistry | volume = 264 | issue = 10 | pages = 5791–8 | date = Apr 1989 | pmid = 2564392 }}
* {{cite journal | vauthors = Whiteheart SW, Shenbagamurthi P, Chen L, Cotter RJ, Hart GW | title = Murine elongation factor 1 alpha (EF-1 alpha) is posttranslationally modified by novel amide-linked ethanolamine-phosphoglycerol moieties. Addition of ethanolamine-phosphoglycerol to specific glutamic acid residues on EF-1 alpha | journal = The Journal of Biological Chemistry | volume = 264 | issue = 24 | pages = 14334–41 | date = Aug 1989 | pmid = 2569467 }}
* {{cite journal | vauthors = Ann DK, Wu MM, Huang T, Carlson DM, Wu R | title = Retinol-regulated gene expression in human tracheobronchial epithelial cells. Enhanced expression of elongation factor EF-1 alpha | journal = The Journal of Biological Chemistry | volume = 263 | issue = 8 | pages = 3546–9 | date = Mar 1988 | pmid = 3346208 }}
* {{cite journal | vauthors = Brands JH, Maassen JA, van Hemert FJ, Amons R, Möller W | title = The primary structure of the alpha subunit of human elongation factor 1. Structural aspects of guanine-nucleotide-binding sites | journal = European Journal of Biochemistry / FEBS | volume = 155 | issue = 1 | pages = 167–71 | date = Feb 1986 | pmid = 3512269 | doi = 10.1111/j.1432-1033.1986.tb09472.x | doi-access = free }}
{{refend}}

== Vanjski linkovi ==
*[https://www.ncbi.nlm.nih.gov/gene/1234 CCR5 - C-C motif chemokine receptor 5 (gene/pseudogene) - Homo sapiens (human)] Information from [https://www.ncbi.nlm.nih.gov/gene/ NCBI Gene Database]
*[http://www.rcsb.org/pdb/explore/jmol.do?structureId=4MBS&bionumber=1 Crystal Structure of the CCR5 Chemokine Receptor] A rotatable, zoomable 3-D image from rcsb.org
*[https://www.pbs.org/wgbh/evolution/library/10/4/l_104_06.html Video and text from a PBS documentary about the discovery of CCR5]
* {{cite web | url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2228 | title = Chemokine Receptors: CCR5 | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | access-date = 16. 3. 2021 | archive-date = 18. 1. 2021 | archive-url = https://web.archive.org/web/20210118033248/https://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2228 | url-status = dead }}
*[https://search.cdc.gov/search/?utf8=%E2%9C%93&affiliate=cdc-main&query=ccr5 HuGENavigator literature on HIV Infections and CCR5] from Centers for Disease Control and Prevention  - (note, authors may not be CDC employees, and there is no public domain notice on the page, so this cannot be assumed to be public domain)
* [http://www.sch-plough.com/schering_plough/news/release.jsp?releaseID=1052027 Schering-Plough Initiates Phase III Studies with CCR5-Vicriviroc in Treatment- Experienced HIV Patients].
* [http://crdd.osdd.net/raghava/hivcopred/ HIVcoPred] A server for prediction of HIV coreceptor usage (CCR5). [http://dx.plos.org/10.1371/journal.pone.0061437 PLoS ONE 8(4): e61437]
* {{UCSC gen info|CCR5}}
* {{PDBe-KB2|P51681|C-C chemokine receptor type 5}}

{{AIDS}}
{{Citokinski receptori}}
{{Klasteri diferencijacije}}
{{Modulatori hemokinskih receptora}}

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