Accessory Genes

From The Gypsy Database

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.

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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 (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 (Steheling et al. 1976; Spector, Varmus and Bishop 1978; 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 (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 (Rosati et al. 2000); we found it is also present in other betaretroviruses described in humans, mice, and primates (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 (Acha-Orbea and Macdonald 1995; Brandt-Carlson and Butel 1991; Choi, Kappler, and Marrack 1991; Choi, Marrack, and Kappler 1992; Krummenacher and Diggelmann 1993; Yazdanbakhsh et al. 1993; 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 (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 (Koralnik et al. 1992). Neither pX-I nor pX-II proteins are required for virus in vitro replication (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 (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" (Yoshida et al. 1995). Also, Simian T-Lymphotropic Virus (STcLV2PP1664) carries an additional accessory gene termed Orf V, displayed adjacent to the 3'LTR (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 (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 (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 (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 (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 (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" (Rabson et al. 1985; Kan et al. 1986; Lee et al. 1986; Sodroski et al. 1986; Oberste and Gonda 1992; Audoly et al. 1992; Wieland et al. 1994). Vif seems to be necessary for the production of infectious viruses (Fan and Peden 1992; Gabuzda et al. 1992; Blanc et al. 1993; Sakai et al. 1993; von Schwedler et al. 1993), and increases the incorporation of "env" proteins into virions (Sakai et al. 1993; 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 (Gabuzda et al. 1992; Madani and Kabat 1998; 2000; Simon et al. 1998; 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 (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 (Guyader et al. 1987; Wong-Staal et al. 1987; Tristem et al. 1992). Two studies suggested that vpx may have arisen from ancient vpr duplication (Sharp et al. 1996; Tristem, Purvis, and Quicke 1998). Both Vpr and Vpx proteins are packaged in the viral particle by various interactions with gag (Lu et al. 1993; Paxton Connors and Landau 1993; Lavallee et al. 1994; Wu et al. 1994; 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 (Bukrinsky et al. 1993;Heinzinger et al. 1994) and also, inducing cell differentiation, arrest, and apoptosis of the infected cell cycle in G2/M (Levi et al. 1993; Rogel et al. 1995; Emerman 1996).In contrast, Vpx incorporates one of these two functions displayed in Vpr (nuclear transport) but does not induce a G2 arrest (Di Marzio et al. 1995; Re et al. 1995; 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 (Planelles et al. 1996).

Vpu is a gene only present in the HIV-1 retrovirus and its related chimpanzee's SIV lentiviruses (Cohen et al. 1988; 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 (Willey et al. 1992a; 1992b; Gottlinger et al. 1993). These two activities of Vpu seem to be regulated by phosphorylation (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 (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 (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 (Gemeniano et al. 2003 and references therein).

Ovine Maedi Visna Virus (SA-OMVV) displays a conserved accessory gene called Orf-W (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 (Bukovsky et al. 1997; 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 (Kestler et al. 1991; Aiken and Trono 1995; Schwartz et al. 1995; Miller et al. 1995; 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 (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 (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 (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 (Cullen et al. 1998; 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 (Mergia et al. 1991; 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 (Saib et al. 1995; 1997).

Danio rerio Foami Virus type 1 (DrFV-1) is a distant putative foamy retrovirus (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.

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