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Vertebrate retroviruses may be divided in simple and complex retroviruses. The main difference consists in that while simple retroviruses present the basal LTR-''gag-pol-env''-LTR genomic structure, complex retroviruses incorporate in their genomes some additional accessory genes that are usually needed to adjust diverse aspects of their replication and infectivity. Accessory genes may be characteristic of a genus, characteristic of a clade within a genus, and in certain cases, exclusive of a unique retrovirus. In this section we provide a brief detail of which accessory genes are typically observed in each particular lineage.

===Alpharetroviruses===
''Lymphoproliferative Disease Virus'' (LPDV) bears in different zones of the internal region four short Open Reading Frames (ORFs) with unclear function, named ORF1, ORF2, ORF3, and ORF4 ([[Literature:66405|Sarid ''et al''. 1994]]).

''Rous Sarcoma Virus'' (RSV) bears a ''src'' oncogene, which codifies for a tyrosine kinase that binds phosphate groups to tyrosine residues in various host cell proteins. This gene is evolutionarily related with a host-native proto-oncogene displayed in certain avian genomes ([[Literature:72235|Steheling ''et al.'' 1976]]; [[Literature:71526|Spector, Varmus and Bishop 1978]]; [[Literature:85407|Bishop 1985]]).

===Betaretroviruses===
Betaretroviruses commonly carry an accessory gene called ''Orf-X'', originally described in the ''Jaagsiekte sheep retrovirus'' (JSRV) and other Endogenous sheep retroviruses (ESRVs). The protein product of this gene has similarity to a portion of the mammalian adenosine receptor subtype 3, which is a member of the G-protein-coupled receptor family ([[Literature:3496|Bai ''et al.'' 1999]]). Although it is unclear yet if the ''Orf-X'' is a functional gene (shows several stops codons in most betaretroviruses), it is well-preserved in both endogenous and exogenous JRSV isolates ([[Literature:64403|Rosati ''et al.'' 2000]]); we found it is also present in other betaretroviruses described in humans, mice, and primates ([[Literature:93206|Llorens ''et al.'' 2008]]). Evidently this indicates that the ''Orf-X'' is a specific phenotype of betaretroviruses, and therefore, that betaretroviruses should be better considered to be complex retroviruses.

''Mouse Mammary Tumor Virus'' (MMTV) incorporates a gene that codifies for a 37-kDa type II transmembrane glycoprotein known as superantigen (sag) that encompasses the U3 3' LTR region overlapping the ''env'' gene. The protein product encoded by the ''sag'' gene is a superantigen that plays a role in determining the T-cell receptor specificity of the retrovirus ([[Literature:85458|Acha-Orbea and Macdonald 1995]]; [[Literature:8517|Brandt-Carlson and Butel 1991]]; [[Literature:13154|Choi, Kappler, and Marrack 1991]]; [[Literature:13153|Choi, Marrack, and Kappler 1992]]; [[Literature:40224|Krummenacher and Diggelmann 1993]]; [[Literature:84698|Yazdanbakhsh ''et al.'' 1993]]; [[Literature:83625|Wrona ''et al.'' 1998]]).

''Simian Retrovirus type 1'' (SRV-1) displays in each LTR a single copy of a putative ORF (''Sorf'') from which little is known ([[Literature:85397|Power ''et al.'' 1986]]). Interestingly, this ORF is also displayed as a three-copy gene tandem in the 3'LTR of the ''Mason-Pfizer Monkey Virus'' (MPMV).

===Deltaretroviruses===
Within a zone of the internal region called "pX" region, deltaretroviruses incorporate several accessory genes coding for distinct regulatory proteins: ORFs pX-I encode for protein called "Rof" and pX-II for another protein named "Tof", which are both generated from single- and double-spliced transcripts ([[Literature:39492|Koralnik ''et al.'' 1992]]). Neither pX-I nor pX-II proteins are required for virus ''in vitro'' replication ([[Literature:17745|Derse ''et al.'' 1997]]) although HTLV-I pX-I and pX-II proteins are chronically synthesized ''in vivo'' and are target for the natural immune response to the virus ([[Literature:59798|Pique ''et al.'' 2000]]). ORFs pX-III encode for a post-transcriptional regulator protein called "Rex", while the pX-IV for a viral transactivator protein called "Tax" ([[Literature:84994|Yoshida ''et al.'' 1995]]). Also, ''Simian T-Lymphotropic Virus'' (STcLV2PP1664) carries an additional accessory gene termed ''Orf V'', displayed adjacent to the 3'LTR ([[Literature:79341|Van Brussel ''et al.'' 1998]]).

===Epsilonretroviruses===
''Walleye Dermal Sarcoma Virus'' (WDSV) contains three short ORFs designated as ''OrfA'', ''OrfB'' and ''OrfC''. Expression of ''OrfA'' inhibits cell growth and/or induces cell death; the first 49 N-terminal residues of the protein product encoded by this gene are enough to cause these effects ([[Literature:74384|Zhang and Martineau 1999]]). The protein product of this gene displays sequence similarity to cyclins A and D and it has been shown to complement a cyclin-deficient yeast strain ([[Literature:31845|Holzschu ''et al.'' 1995]]). The ORFC protein is encoded as a full-length genomic transcript that can be detected in tumor extracts and is targeted to mitochondria, wherein it plays a functional role in an alteration of mitochondrial function that results in apoptosis, contributing to tumor regression ([[Literature:55316|Nudson ''et al.'' 2003]]). Transcripts of ORFA and ORFB have also been detected in tumors.

''Xenopus laevis endogenous retrovirus'' (XEN 1) displays two relatively short ORFs encoding protein products of 109 and 132 amino acids (aa), respectively ([[Literature:35936|Kambol ''et al.'' 2003]]), both with a phosphorylase function. The two ORFs appear to have arisen via gene duplication, as they are 36% identical at the amino acid level ([[Literature:35936|Kambol ''et al.'' 2003]]). Our sequence analysis has revealed that these accessory genes have not homology with any known no date ''Retroviridae'' accessory gene.

===Lentiviruses===
Except ''Equine Infectious Anemia Virus'' (EIAV), all known to date lentiviruses have an accessory gene downstream to the ''pol'' gene that codify for a "Viral infectivity factor" (Vif) protein of 23-kDa, also termed "Sor" or "ORFQ" ([[Literature:61742|Rabson ''et al.'' 1985]]; [[Literature:36026|Kan ''et al.'' 1986]]; [[Literature:42638|Lee ''et al.'' 1986]]; [[Literature:70948|Sodroski ''et al.'' 1986]]; [[Literature:55646| Oberste and Gonda 1992]]; [[Literature:2887|Audoly ''et al.'' 1992]]; [[Literature:82653| Wieland ''et al.'' 1994]]). Vif seems to be necessary for the production of infectious viruses ([[Literature:21249|Fan and Peden 1992]]; [[Literature:23938|Gabuzda ''et al.'' 1992]]; [[Literature:6946|Blanc ''et al.'' 1993]]; [[Literature:65767|Sakai ''et al.'' 1993]]; [[Literature:78993| von Schwedler ''et al.'' 1993]]), and increases the incorporation of "env" proteins into virions ([[Literature:65767|Sakai ''et al.'' 1993]]; [[Literature:7850|Borman ''et al.'' 1995]]). Particularly, the Vif product encoded by the HIV-1 retrovirus has been reported to be essential for the productive infection of primary human CD4 T-lymphocytes and macrophages. ''In vitro'', Vif-defective HIV-1 strains are capable of replicating in permissive cells but not in nonpermissive cells ([[Literature:23938|Gabuzda ''et al.'' 1992]]; [[Literature:46051|Madani and Kabat 1998]]; [[Literature:46050|2000]]; [[Literature:70031|Simon ''et al.'' 1998]]; [[Literature:78993|von Schewedler ''et al.'' 1993]]). It has been suggested that Vif may assist other proteins in keeping the adequate folding of genomic RNAs in the package process, and also in the reverse transcription process ([[Literature:30483|Henriet ''et al.'' 2005]]).

"Viral protein r" (Vpr) and "Viral protein x" (Vpx) are two small related proteins encoded by primate lentiviruses. The genes coding for these two proteins are present in HIV-2 and its closely related SIVMAC retrovirus described in primates. In contrast, only the ''vpr'' gene is found in the HIV-1 retrovirus and most other SIV strains ([[Literature:28410|Guyader et al. 1987]]; [[Literature:83421|Wong-Staal ''et al.'' 1987]]; [[Literature:77745|Tristem ''et al.'' 1992]]). Two studies suggested that ''vpx'' may have arisen from ancient ''vpr'' duplication ([[Literature:68836|Sharp ''et al.'' 1996]]; [[Literature:77739|Tristem, Purvis, and Quicke 1998]]). Both Vpr and Vpx proteins are packaged in the viral particle by various interactions with gag ([[Literature:45260|Lu ''et al.'' 1993]]; [[Literature:58303|Paxton Connors and Landau 1993]]; [[Literature:42043|Lavallee ''et al.'' 1994]]; [[Literature:83748|Wu ''et al.'' 1994]]; [[Literature:32095|Horton, Spearman, and Ratner 1994]]). Vpr has also be shown to play a role targeting the viral-preintegration-complex to the nucleus of nondividing cells ([[Literature:9607|Bukrinsky ''et al.'' 1993]];[[Literature:30277|Heinzinger ''et al.'' 1994]]) and also, inducing cell differentiation, arrest, and apoptosis of the infected cell cycle in G2/M ([[Literature:43314|Levi ''et al.'' 1993]]; [[Literature:64104|Rogel ''et al.'' 1995]]; [[Literature:20342|Emerman 1996]]).In contrast, Vpx incorporates one of these two functions displayed in Vpr (nuclear transport) but does not induce a G2 arrest ([[Literature:18088|Di Marzio ''et al.'' 1995]]; [[Literature:62433|Re ''et al.'' 1995]]; [[Literature:22501|Fletcher ''et al.'' 1996]]). The exception is the Vpx product encoded by ''Simian immunodeficiency virus'' (SIVAGM) that has been empirically demonstrated to be capable of inducing arrest in CV-1 ([[Literature:59958|Planelles ''et al.'' 1996]]).

''Vpu'' is a gene only present in the HIV-1 retrovirus and its related chimpanzee's SIV lentiviruses ([[Literature:14052|Cohen ''et al.'' 1988]]; [[Literature:85506|Myers ''et al.'' 1994]]). ''Vpu'' encodes for a small intracellular protein called "Viral protein u" (Vpu) that causes degradation of newly synthesized CD4 and also plays a role in viral assembly and release of the retrovirus ([[Literature:82868|Willey ''et al.'' 1992a]]; [[Literature:82867|1992b]]; [[Literature:26891|Gottlinger ''et al.'' 1993]]). These two activities of Vpu seem to be regulated by phosphorylation ([[Literature:67566|Schubert and Strebel 1994]]).

Genomes of several non-primate lentiviruses bear ORFs for certain genes such as ''Orf-S2'' in the case of EIAV, or ''tmx'', ''vpy'' and ''vpw'' in the case of ''Bovine Immunodeficiency Virus'' (BIV) whose function is still unclear. Despite this, a study indicates that ORF-S2 is not required for viral infectivity or replication ([[Literature:43516|Li, Puffer, and Montelaro 1998]]), and it has also been suggested that the protein products encoded by ''tmx'', ''vpy'' and ''vpr'' might be analogues of Nef, Vpr/Vpx and Vpu proteins ([[Literature:26489|Gonda ''et al.'' 1994]]).

The ''Orf-A'', also known ''Orf-2'', is a accessory gene present in the genome of the ''Feline Immunodeficiency Virus'' (FIV) that codifies for a small transcriptional trans-activator protein needed for infectivity and efficient replication of this retrovirus in primary T-lymphocytes ([[Literature:25091|Gemeniano ''et al.'' 2003 ]]and references therein).

''Ovine Maedi Visna Virus'' (SA-OMVV) displays a conserved accessory gene called ''Orf-W'' ([[Literature:61531|Querat ''et al.'' 1990]]) that we have found it is also conserved but corrupted in other visna viruses such as VMV and CAEV.

''Nef'' is an accessory gene found only in primate lentiviruses. This gene maps adjacent to the 3´LTR and codifies for a protein called "Negative factor" (Nef), which is a myristylated intracellular protein that reduces interactions between env and intracellular CD4 antigens ([[Literature:9579|Bukovsky ''et al.'' 1997]]; [[Literature:59577|Piguet ''et al.'' 1999]]). Nef is necessary for viral infectivity ''in vivo'' but not ''in vitro'', and also increases the efficiency of reverse transcription and infectivity of a retrovirus ([[Literature:37458|Kestler ''et al.'' 1991]]; [[Literature:703|Aiken and Trono 1995]]; [[Literature:67774|Schwartz ''et al.'' 1995]]; [[Literature:50420|Miller ''et al.'' 1995]]; [[Literature:26333|Goldsmith ''et al.'' 1995]]). Nef also downregulates the cell surface expression of MHC I molecules and protects infected cells from cytotoxic T-lymphocytes-induced death ([[Literature:14383|Collins ''et al.'' 1998]]).

''Tat'' and ''rev'' are two accessory genes coding for two transactivator proteins necessary for viral replication and the enhancement of the production of viral mRNAs.
''Tat'' is present in all lentiviruses, except FIV ([[Literature:20170|Elder ''et al.'' 1998]]). The encoded product of ''tat'' is a low-molecular-weight protein that activates the transcription of the retrovirus by binding to the "Tat Activation Region" (TAR) located at the 5' end of all viral mRNAs. To be active, tat binds to the cyclin-dependent kinase (Cdk)-Cyclin T complex ([[Literature:82001|Wei ''et al.'' 1998]]). ''Rev'' is also present in all lentiviruses; its protein product harbors a "nuclear localization signal" (NLS) and a "nuclear export signal" (NES) and binds to the "Rev Responsive Element" (RRE) -an RNA secondary structural element within the ''env'' gene- to join the viral RNA. ''Rev'' also facilitates the transport of unspliced and incompletely spliced mRNAs to the cytoplasm ([[Literature:15629|Cullen ''et al.'' 1998]]; [[Literature:60283|Pollard ''et al.'' 1998]]).

===Spumaretroviruses===
Spumaretroviruses usually codify for two common accessory genes: ''bel1'' and ''bel2''. The first encodes for a protein product "Tas", which is a trans-activator factor that stimulates transcription by binding to specific sites of the LTRs ([[Literature:49786|Mergia ''et al.'' 1991]]; [[Literature:63008|Rethwilm ''et al.'' 1991]]). Little is known about ''bel2'' but it is known that it encodes a fusion protein ("Bet" or "Bel3") together with ''bel1'' that is expressed at high levels in infected cells, and plays a role in the establishment and control of viral persistence, both ''in vitro'' and ''in vivo'' ([[Literature:65660|Saib ''et al.'' 1995]]; [[Literature:65657|1997]]).

''Danio rerio Foami Virus type 1'' (DrFV-1) is a distant putative foamy retrovirus ([[Literature:100596|Llorens ''et al.'' 2009]]) displaying the typical gag and pol ORFs and three additional ORFs that show no similarity to any sequence known to date (including env). DrFV-1 is taxonomically important because it is unclear if it is a true retrovirus carrying a highly divergent ''env'' plus two accessory or additional genes or a LTR retrotransposon intermediate between the ''Ty3/Gypsy'' and the ''Retroviridae'' carrying three additional genes.

[[Category:Retroelements]]

Accessory Genes - Revision history

imported>Gydbwiki at 14:16, 29 April 2010