“…Simple retroviruses, such as γ-retroviruses, contain only four basic genes, gag, pro, pol, and env. These genes are necessary for the viral particle production, assembly, and post-entry processing that eventually lead to proviral integration ( Chameettachal et al, 2023 ). Gag encodes a precursor protein processed into the mature MA (matrix), CA (capsid), and NC (nucleocapsid) proteins.…”
Stem cells have been widely applied in regenerative and therapeutic medicine for their unique regenerative properties. Although much research has shown their potential, it remains tricky in directing stem cell differentiation. The advancement of genetic and therapeutic technologies, however, has facilitated this issue through development of design molecules. These molecules are designed to overcome the drawbacks previously faced, such as unexpected differentiation outcomes and insufficient migration of endogenous or exogenous MSCs. Here, we introduced aptamer, bacteriophage, and biological vectors as design molecules and described their characteristics. The methods of designing/developing discussed include various Systematic Evolution of Ligands by Exponential Enrichment (SELEX) procedures, in silico approaches, and non-SELEX methods for aptamers, and genetic engineering methods such as homologous recombination, Bacteriophage Recombineering of Electroporated DNA (BRED), Bacteriophage Recombineering with Infectious Particles (BRIP), and genome rebooting for bacteriophage. For biological vectors, methods such as alternate splicing, multiple promoters, internal ribosomal entry site, CRISPR-Cas9 system and Cre recombinase mediated recombination were used to design viral vectors, while non-viral vectors like exosomes are generated through parental cell-based direct engineering. Besides that, we also discussed the pros and cons, and applications of each design molecule in directing stem cell differentiation to illustrate their great potential in stem cells research. Finally, we highlighted some safety and efficacy concerns to be considered for future studies.
“…Simple retroviruses, such as γ-retroviruses, contain only four basic genes, gag, pro, pol, and env. These genes are necessary for the viral particle production, assembly, and post-entry processing that eventually lead to proviral integration ( Chameettachal et al, 2023 ). Gag encodes a precursor protein processed into the mature MA (matrix), CA (capsid), and NC (nucleocapsid) proteins.…”
Stem cells have been widely applied in regenerative and therapeutic medicine for their unique regenerative properties. Although much research has shown their potential, it remains tricky in directing stem cell differentiation. The advancement of genetic and therapeutic technologies, however, has facilitated this issue through development of design molecules. These molecules are designed to overcome the drawbacks previously faced, such as unexpected differentiation outcomes and insufficient migration of endogenous or exogenous MSCs. Here, we introduced aptamer, bacteriophage, and biological vectors as design molecules and described their characteristics. The methods of designing/developing discussed include various Systematic Evolution of Ligands by Exponential Enrichment (SELEX) procedures, in silico approaches, and non-SELEX methods for aptamers, and genetic engineering methods such as homologous recombination, Bacteriophage Recombineering of Electroporated DNA (BRED), Bacteriophage Recombineering with Infectious Particles (BRIP), and genome rebooting for bacteriophage. For biological vectors, methods such as alternate splicing, multiple promoters, internal ribosomal entry site, CRISPR-Cas9 system and Cre recombinase mediated recombination were used to design viral vectors, while non-viral vectors like exosomes are generated through parental cell-based direct engineering. Besides that, we also discussed the pros and cons, and applications of each design molecule in directing stem cell differentiation to illustrate their great potential in stem cells research. Finally, we highlighted some safety and efficacy concerns to be considered for future studies.
“…The HIV-1 virion has a spherical shape with a diameter of 120 nm (top right; Figure 1 ). The virion contains two copies of a single-stranded long positive-sense RNA genome, each of which consists of 10,000 nucleotides [ 23 ]. These two copies of the HIV-1 RNA genome, along with the viral replication enzymes, namely the reverse transcriptase (RT), integrase (IN), and nucleocapsid (NC) protein, are encapsulated in the conically-shaped mature capsid (CA) core (top right; Figure 1 ) [ 24 ].…”
“…The key early steps include binding to the cell membrane, cell entry (fusion), reverse transcription, nucleus import, and the integration of the viral genome into the host-cell genome ( Figure 1 ) [ 26 ]. Likewise, the late steps include the transcription step for producing the viral gRNA and the viral messenger RNAs (mRNAs), nuclear export of the newly transcribed RNAs, translation, dimerization and packaging of the gRNA strands, assembly of the new virus particle on the cell membrane, and finally the release of the virus particle for further maturation ( Figure 1 ) [ 23 , 25 ]. Figure 1.…”
“…TAR RNA adopts an A-form helical stem loop with a three-nucleotide bulge motif that divides the structure into two helices (Helix 1 and Helix 2) and capped by an apical loop ( Figure 3A ). The arginine rich motif (ARM) of the Tat protein recognizes TAR RNA near the bulge motif and further recruits the host-cell super elongation complex (SEC) [ 23 ]. SEC includes two complexes, the positive transcript elongation factor b (P-TEFb) complex which contains CDK9 and cyclin T1 and the polymerase-associated factor 1 (PAF-1) complex [ 23 ].…”
Section: Structural and Biochemical Studies On Hiv-1 Tar Rnamentioning
Viruses remain a global threat to animals, plants, and humans. The type 1 human immunodeficiency virus (HIV-1) is a member of the retrovirus family and carries an RNA genome, which is reverse transcribed into viral DNA and further integrated into the host-cell DNA for viral replication and proliferation. The RNA structures from the HIV-1 genome provide valuable insights into the mechanisms underlying the viral replication cycle. Moreover, these structures serve as models for designing novel therapeutic approaches. Here, we review structural data on RNA from the HIV-1 genome as well as computational studies based on these structural data. The review is organized according to the type of structured RNA element which contributes to different steps in the viral replication cycle. This is followed by an overview of the HIV-1 transactivation response element (TAR) RNA as a model system for understanding dynamics and interactions in the viral RNA systems. The review concludes with a description of computational studies, highlighting the impact of biomolecular simulations in elucidating the mechanistic details of various steps in the HIV-1’s replication cycle.
“…HIV-1 Tat increases the processivity of the host’s RNA polymerase II [ 6 , 7 ] by recruiting the host’s super elongation complex (SEC) [ 8 ]. The SEC includes the heterodimer positive transcription elongation factor-b (P-TEFb) complex comprising Cyclin T1 and CDK9 [ 9 , 10 , 11 , 12 , 13 , 14 ], and the polymerase-associated factor 1 (PAF-1) complex [ 15 , 16 ] to the transacting responsive region (TAR). Located downstream of the initiation site for HIV-1 transcription (nucleotides +1 to +59), TAR adopts an A-form stem-loop structure with a bulge [ 4 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ].…”
Viruses provide vital insights into gene expression control. Viral transactivators, with other viral and cellular proteins, regulate expression of self, other viruses, and host genes with profound effects on infected cells, underlying inflammation, control of immune responses, and pathogenesis. The multifunctional Tat proteins of lentiviruses (HIV-1, HIV-2, and SIV) transactivate gene expression by recruiting host proteins and binding to transacting responsive regions (TARs) in viral and host RNAs. SARS-CoV-2 nucleocapsid participates in early viral transcription, recruits similar cellular proteins, and shares intracellular, surface, and extracellular distribution with Tat. SARS-CoV-2 nucleocapsid interacting with the replication–transcription complex might, therefore, transactivate viral and cellular RNAs in the transcription and reactivation of self and other viruses, acute and chronic pathogenesis, immune evasion, and viral evolution. Here, we show, by using primary and secondary structural comparisons, that the leaders of SARS-CoV-2 and other coronaviruses contain TAR-like sequences in stem-loops 2 and 3. The coronaviral nucleocapsid C-terminal domains harbor a region of similarity to TAR-binding regions of lentiviral Tat proteins, and coronaviral nonstructural protein 12 has a cysteine-rich metal binding, dimerization domain, as do lentiviral Tat proteins. Although SARS-CoV-1 nucleocapsid transactivated gene expression in a replicon-based study, further experimental evidence for coronaviral transactivation and its possible implications is warranted.
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