HIV-1 rev and tat fragments
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Two HIV proteins, called TAT and REV, are important positive regulators of gene expression. Both of them regulate the expression of virus gene by interacting with 5' untranslated leading sequence and RNA target element in envelope gene, respectively. The fully spliced transcripts are exported from the nucleus to the cytoplasm, and the mechanism is the same as that of cell mRNA. Most recent studies have shown that these interactions alone are not sufficient to provide regulation without additional host cytokines.
Introduction of Rev
Rev, with a molecular weight of 13 KD, is a sequence-specific RNA-binding protein encoded by mRNA completely cut by HIV, which induces the transition of HIV gene expression from early stage to late stage. Rev aggregates in the nucleus and nucleolus of infected cells and binds to a 240-base-long region of RNA called Rev Response Element (RRE), facilitating the transport of incomplete RNA from the nucleus to the cytoplasm. RNA containing introns (such as uncut or incomplete cut RNA) is usually stranded in the nucleus. High expression of Rev can promote the nucleation of RNA containing introns, resulting in a decrease in the number of RNA used for complete cleavage in the nucleus, which reduces the expression of Rev. The ability of Rev to reduce the shear efficiency of RNA forms a negative feedback regulation cycle, which makes the expression level of Rev itself be accurately regulated.
Introduction of TAT
TAT is a transcriptional trans-activator, which has 72 amino acids or 101 amino acids and encoded by HIV early complete shear mRNA and late incomplete shear mRNA, respectively. Both forms of Tat exist in the nuclei and nucleolus of infected cells. Traditional transcription factors bind to DNA, while TAT binds to RNA. At the 5' end of the HIV there is a short stem-loop structure called the trans-activating response element (TAR). TAT can up-regulate the transcription of HIV more than 1000 times by binding to TAR.
Conclusion
Due to the development of human immunodeficiency virus-1 (HIV-1) resistance to current antiviral drugs and the known toxicity of many of them, it is clear that it is necessary to identify and develop new compounds for the treatment of patients with HIV-1 infection. The regulatory proteins TAT and REV of HIV-1 are necessary for HIV-1 replication, so they are two important viral targets for drug development. New drugs targeting these proteins will increase the number of effective treatment strategies for HIV-1 infection. This may lead to better combination therapy, in which many different viral targets can be suppressed at the same time, reducing the likelihood of selecting drug-resistant viruses.
References
- Weeks, K. M., Ampe, C., Schultz, S. C., Steitz, T. A., & Crothers, D. M. (1990). Fragments of the HIV-1 Tat protein specifically bind TAR RNA. Science, 249(4974), 1281-1285.
- Mueller, N., Pasternak, A. O., Klaver, B., Cornelissen, M., Berkhout, B., & Das, A. T. (2018). The HIV-1 Tat protein enhances splicing at the major splice donor site. Journal of virology, 92(14), e01855-17.
