Viral transactivator

The viral protein Rev may also play a role in HIV-1 latency. Expression of the viral Rev protein is essential for the nuclear export of genomic RNA as well as unspliced and/or singly spliced transcripts (Cullen 2003), which are ultimately translated into structural, regulatory, and enzymatic viral proteins. Retention of Rev and Tat (viral transactivator proteins) transcripts in the nucleus of resting CD4h- T cells from HAART patients (Lassen et al. 2006) might be involved in the maintenance of post-integration latency in these cells. Importantly, this phenomenon is non-existent in activated T cells. 

EBNAl encodes a nuclear antigen vdth promoter activity functioning as the main viral transactivator. 

Primers for the amplification of EBV gene fragment encoding a major viral transactivator ... 

Herpes simplex virus (HSV) has been the most extensively studied of the human herpesviruses owing to its ability to easily infect cells in vitro to produce infectious virus. As with all herpesviruses, HSV encodes a number of proteins for efficient viral gene expression, viral DN A replication, and the shutoff of cellular gene transcription and translation [53], These virally expressed proteins do not function in isolation but associate with a variety of cellular and viral proteins. Furthermore, many have exhibited multiple different functions. In an effort to understand the biology of HSV and the function of its proteins, a proteomics approach has been used to study a critical viral transactivator (ICP27), the alteration of the cellular translation machinery, and components of the viral replication complex, which will be reviewed here. 

EnsoK B, Buonaguro L, Barillari G, et al. Release, uptake, and effects of extracellular human immunodeficiency virus type 1 Tat protein on cell growth and viral transactivation. / Virol. 1993 67(l) 277-287. 

The transactivation-responsive region (TAR) is located immediately downstream of the transcriptional start site in the HIV-1 LTR, encompassing nucleotides h-1 to h-59 (Berkhout et al. 1989 Muesing et al. 1987), and is reqnired for the function of the viral trans-activator protein Tat. In the absence of Tat (Fig. 5.2b), short transcripts... 

Marzio G, Tyagi M, Gutierrez MI, Giacca M (1998) HIV-1 tat transactivator recruits p300 and CREB-binding protein histone acetyltransferases to the viral promoter. Proc Natl Acad Sd USA95(23) 13519-13524... 

Other HIV proteins include regulator of viral expression (Rev), negative effectors (Nef), viral protein R (Vpr), viral protein U (Vpu), viral infectivity factor (Vif) and transactivator protein (Tat). These proteins are instrumental in viral mRNA expression, viral replication and transactivation, viral release and maturation, viral infection, and maintenance of viral transcript activation and expression, respectively (Tripathi and Agrawal 2007). 

The absence of a transactivation-competent NF-kB heterodimer in the nucleus of latently infected resting memory CD4+ T cells could contribute to latency. Activation of the NF-kB pathway leading to migration of a transactivating heterodimer such as p50/p65 could allow viral reactivation. In the absence of induction, NF-kB p50-HDACl complexes constitutively bind the latent HIV-1 LTR (Williams et al, 2006). NF-kB p50 does not possess a transactivation domain. These p50-HDACl complexes induce histone deacetylation and repressive changes in chromatin structure of the HIV-1 LTR (Williams et al, 2006). Knockdown of p50 expression reduces HDACl binding to the latent HIV-1 LTR and induces RNA polymerase II recruitment (Williams et al, 2006). Concomitantly with HIV-1 transcriptional activation, the p65 subunit and different HATs are recruited to the viral promoter (Lusic et al, 2003 Thierry et al, 2004). 

An example of this class of peptide is the 86-amino acid truKi-activating transcriptional activator (TAT) of HIV-1 (74,75). Following incubation with cultured cells, TAT protein is internalized and subsequently transactivates viral promoters (75). The protein has multiple facets invasion, nuclear trophism, and DNA binding (76-81). An invasion domain of TAT has been identified within amino acids 37 to 72 with the critical basic region from amino acids (49 to 57), also known as the minimal transduction domain, which consists of the sequence -Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-. Any deletion in the sequence caused a reduction in translocating activity (82-84). Other prominent CPPs are reviewed in References 73 and 85. 

Figure 2.3 Tetracycline regulated gene expression (Adapted from Applied Molecular Genetics, R.Miesfeld, Wiley publishing, New York, 1999, p. 190). Terminology CMV (cytomegalovirus) VP (activating domain of viral protein VP 16) fefR (Tet represser) tTA (tetracycline-regulated trans-activator protein) rtTA (reverse let transactivator protein) (tel())- (repeat of 7 tet operator sequences) TATA (transcription initiation consensus sequence).

A number of products exist that are targeted at any of the successive events implicated in the replicative cycle of HIV virus entry, viral adsorption, virus-cell fusion, reverse (RNA —> DNA) transcription, proviral DNA integration, viral (DNA —> RNA) transcription (transactivation), viral (mRNA —> protein) translation, virus release, viral assembly, budding, and maturation... 

Christensen, J., Cotmore, S. F., and Tattersall, P. (1995). Minute virus of mice transcriptional activator protein NSl binds directly to the transactivation region of the viral P38 promoter in a strictly ATP-dependent manner./. Virol. 69, 5422-5430. 

Oncoretroviruses are simple viruses encoding only the structural genes gag, pol, and env, whereas lentiviruses and spumaviruses have a more complex organization and encode for additional viral proteins (Figure 2). Lentiviruses encode three to six additional viral proteins that are essential for vims replication and persistence of infection. Two of the accessory proteins, tat and rev, are present in all lentiviruses and mediate transactivation of viral transcription (31,32) and nuclear export of unspliced viral RNA, respectively (33). Spumaviruses, also called foamy viruses (FV), contain, in addition to the structural proteins, three ORFs (taslbell, bel-2, and bel-3), of which taslbell has been identified as a coactivator of viral transcription (34). 

The HSV-1 virion is approximately 20 run in diameter and consists of four components envelope, tegument, capsid, and viral genome. The envelope is derived from the cellular membrane and contains approximately 12 viral glycoproteins essential for viral entry. The tegument is the protein layer between the capsid and the envelope and contains at least 10 viral proteins, including VP 16 (essential for transactivation and virion envelopment), VP22 (membrane translocation domain), and virion host shut off (vhs) protein. The capsid consists of 7 viral proteins and contains the linear dsDNA genome, which is 152 kb in size. 

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