Env (gene): Difference between revisions

Analysis of the structure and sequence of several different ''env'' genes suggests that '''Env''' proteins are [[Fusion_mechanism#Class_I_Fusogens|type 1 fusion machinesmachine]]s.<ref name="pmid9707417">{{cite journal |vauthors=Caffrey M, Cai M, Kaufman J, Stahl SJ, Wingfield PT, Covell DG, Gronenborn AM, Clore GM | title = Three-dimensional solution structure of the 44 kDa ectodomain of SIV gp41 | journal = EMBO J. | volume = 17 | issue = 16 | pages = 4572–84 |date=August 1998 | pmid = 9707417 | pmc = 1170787 | doi = 10.1093/emboj/17.16.4572 }}</ref> Type 1 fusion machines initially bind a receptor on the target cell surface, which triggers a [[conformational change]], allowing for binding of the [[fusion protein]]. The [[fusion peptide]] inserts itself in the host cell membrane and brings the host cell membrane very close to the viral membrane to facilitate membrane fusion.<ref name="pmid12671653">{{cite journal |vauthors=Colman PM, Lawrence MC | title = The structural biology of type I viral membrane fusion | journal = Nat. Rev. Mol. Cell Biol. | volume = 4 | issue = 4 | pages = 309–19 |date=April 2003 | pmid = 12671653 | doi = 10.1038/nrm1076 | s2cid = 31703688 }}</ref>

While there are significant differences in sequence of the ''env'' gene between retroviruses[[retrovirus]]es, the gene is always located downstream of ''[[group-specific antigen|gag]]'', ''pro'', and ''[[pol (HIV)|pol]]''. The ''env'' [[Messenger RNA|mRNA]] must be [[RNA splicing|spliced]] for expression.

The retroviral glycoproteins are oligomeric complexes that are composed of SU-TM [[heterodimer]]s, which are made in the [[endoplasmic reticulum]] after the translation of the glycosylated Env precursor.<ref name="pmid2847170">{{cite journal |vauthors=Einfeld D, Hunter E | title = Oligomeric structure of a prototype retrovirus glycoprotein | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 85 | issue = 22 | pages = 8688–92 |date=November 1988 | pmid = 2847170 | pmc = 282525 | doi =10.1073/pnas.85.22.8688 | bibcode = 1988PNAS...85.8688E | doi-access = free }}</ref> The arrangement of these heterodimers determines the 3D structure of the knobbed spike on the viral surface. The Env proteins of the Avian Sarcoma and Leukosis virus ([[Avian sarcoma leukosis virus|ASLV]]) and the Murine Leukemia Virus ([[Murine leukemia virus|MLV]]) are both trimers of SU-TM heterodimers.<ref name="pmid1887590">{{cite journal |vauthors=Kamps CA, Lin YC, Wong PK | title = Oligomerization and transport of the envelope protein of Moloney murine leukemia virus-TB and of ts1, a neurovirulent temperature-sensitive mutant of MoMuLV-TB | journal = Virology | volume = 184 | issue = 2 | pages = 687–94 |date=October 1991 | pmid = 1887590 | doi =10.1016/0042-6822(91)90438-H }}</ref> The Env protein of Human Immunodeficiency Virus ([[HIV]]) also has a trimeric structure of heterodimers.<ref name="pmid22807678">{{cite journal |vauthors=Tran EE, Borgnia MJ, Kuybeda O, Schauder DM, Bartesaghi A, Frank GA, Sapiro G, Milne JL, Subramaniam S | title = Structural mechanism of trimeric HIV-1 envelope glycoprotein activation | journal = PLoSPLOS Pathog. | volume = 8 | issue = 7 | pages = e1002797 | year = 2012 | pmid = 22807678 | pmc = 3395603 | doi = 10.1371/journal.ppat.1002797 | doi-access = free }}</ref> It is believed that the intracellular transport of the nascent protein depends, to some extent, on the oligomerization of Env precursors, which allows hydrophobic sequences to be buried inside the protein structure. This oligomerization has also been implicated in fusion initiation with the membrane of the target cell.<ref name="pmid1501294">{{cite journal |vauthors=Earl PL, Doms RW, Moss B | title = Multimeric CD4 binding exhibited by human and simian immunodeficiency virus envelope protein dimers | journal = J. Virol. | volume = 66 | issue = 9 | pages = 5610–4 |date=September 1992 | pmid = 1501294 | pmc = 289124 | doi = 10.1128/JVI.66.9.5610-5614.1992}}</ref>

The ''env'' gene codes for the gp160 protein which forms a homotrimer, and is cleaved into gp120 and gp41 by the host cell [[protease]], [[furin]]. To form an active fusion protein, SU gp120 and TM gp41 polypeptides remain non-covalently bound together, but this interaction is often not stable, leading to shed, soluble gp120 and membrane-bound, gp41 'stumps'. Separately, cleavage by furin is inefficient, and virions often are released with inactive, uncleaved gp160. Because of the high prevalence of these inactive forms, the immune system often produces [[antibodies]] which target inactive Envgp160, rather than active forms of the envelope protein. ''See [[HIV#Replication cycle|Replication cycle of HIV]].''

''Env'' expression is regulated by the gene product of ''[[Rev (HIV)|rev]]''. Experimental deletion of ''rev'' resulted in the inability to detect the Env protein and levels of ''env'' mRNA in the cell cytoplasm were significantly diminished. However, when total cellular RNA was analyzed, ''env'' RNA totals were not significantly differencedifferent in the presence and absence of ''rev'' coexpression. It was found that without ''rev'' expression, there was a marked increase in nuclear ''env'' RNA, which suggests that ''rev'' plays an important role in the nuclear export of ''env'' mRNA.<ref name="Hammarskjöld_1989">{{cite journal |vauthors=Hammarskjöld ML, Heimer J, Hammarskjöld B, Sangwan I, Albert L, Rekosh D | title = Regulation of human immunodeficiency virus env expression by the rev gene product | journal = J. Virol. | volume = 63 | issue = 5 | pages = 1959–66 |date=May 1989 | pmid = 2704072 | pmc = 250609 | doi = 10.1128/JVI.63.5.1959-1966.1989}}</ref> The role of ''rev'' was further elucidated when it was found that Rev''rev'' acts [[in trans]] to target a specific sequence present in the ''env'' gene of HIV-1 to initiate export of incompletely spliced HIV-1 RNA from the nucleus.<ref name="pmid2784194">{{cite journal |vauthors=Malim MH, Hauber J, Le SY, Maizel JV, Cullen BR | title = The HIV-1 rev trans-activator acts through a structured target sequence to activate nuclear export of unspliced viral mRNA | journal = Nature | volume = 338 | issue = 6212 | pages = 254–7 |date=March 1989 | pmid = 2784194 | doi = 10.1038/338254a0 |bibcode = 1989Natur.338..254M | s2cid = 4367958 }}</ref>

Exposed on the surface of the viral envelope, the [[glycoprotein]] gp120 binds to the [[CD4]] [[receptor (biochemistry)|receptor]] on any target cell that has such a receptor, particularly the [[helper T-cell]]. See [[HIV#Tropism|HIV tropism]] and [[HIV#Replication cycle|Replication cycle of HIV]]. Strains of HIV-1 have been isolated that are able to enter host cells that are CD4 negative.{{Citation needed|date=February 2013}} This CD4-independence is associated with spontaneous mutation in the ''env'' gene. The presence of a [[Coreceptor|co-receptor]], CXCR₄, is sufficient for this mutant strain to infect human cells. The strain with this [[phenotype]] was found to have seven mutations in the sequence coding for gp120 and it is proposed that these mutations induce conformational changes in gp120 that allow the virus to directly interact with the co-receptor.<ref name="pmid9420253">{{cite journal |vauthors=Dumonceaux J, Nisole S, Chanel C, Quivet L, Amara A, Baleux F, Briand P, Hazan U | title = Spontaneous mutations in the env gene of the human immunodeficiency virus type 1 NDK isolate are associated with a CD4-independent entry phenotype | journal = J. Virol. | volume = 72 | issue = 1 | pages = 512–9 |date=January 1998 | pmid = 9420253 | pmc = 109402 | doi = 10.1128/JVI.72.1.512-519.1998}}</ref>

[[Fusion inhibitor]] drugs such as [[enfuvirtide]] block the fusion process by binding to gp41.<ref name="pmid12637625">{{cite journal |author9-link=Daniel Kuritzkes|vauthors=Lalezari JP, Henry K, O'Hearn M, Montaner JS, Piliero PJ, Trottier B, Walmsley S, Cohen C, Kuritzkes DR, Eron JJ, Chung J, DeMasi R, Donatacci L, Drobnes C, Delehanty J, Salgo M | title = Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America | journal = N. Engl. J. Med. | volume = 348 | issue = 22 | pages = 2175–85 |date=May 2003 | pmid = 12637625 | doi = 10.1056/NEJMoa035026 | doi-access = free }}</ref>

The ''env'' gene of [[Murine leukemia virus|Murine Leukemia Virus]] (MLV) codes for the 71,000-dalton glycoprotein, gp71. This membrane receptor was isolated from Rauscher murine leukemia virus (R-MuLV).<ref name="pmid8213">{{cite journal |vauthors=DeLarco J, Todaro GJ | title = Membrane receptors for murine leukemia viruses: characterization using the purified viral envelope glycoprotein, gp71 | journal = Cell | volume = 8 | issue = 3 | pages = 365–71 |date=July 1976 | pmid = 8213 | doi =10.1016/0092-8674(76)90148-3 | s2cid = 45192638 }}</ref>

The retroviral protein env has been captured multiple times during [[mammalian evolution]] and is expressed in placental tissue, where it facilitates fusion of fetal and maternal cells. The protein is called [[syncytin]] in mammals.<ref>Nova. 2016. Endogenous retroviruses. Retrieved from https://www.pbs.org/wgbh/nova/next/evolution/endogenous-retroviruses</ref><ref name="pmid23938756">{{cite journal | vauthors = Lavialle C, Cornelis G, Dupressoir A, Esnault C, Heidmann O, Vernochet C, Heidmann T | title = Paleovirology of 'syncytins', retroviral env genes exapted for a role in placentation | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 368 | issue = 1626 | pages = 20120507 | date = September 2013 | pmid = 23938756 | pmc = 3758191 | doi = 10.1098/rstb.2012.0507 }}</ref>

[[Category:Viral structural proteins]]