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The New Microbiologica Apr 2005Many studies have demonstrated that HIV-1 Tat plays a pivotal role both in the HIV-1 replication cycle and in the pathogenesis of HIV-1 infection. Indeed, Tat affects... (Review)
Review
Many studies have demonstrated that HIV-1 Tat plays a pivotal role both in the HIV-1 replication cycle and in the pathogenesis of HIV-1 infection. Indeed, Tat affects the HIV-1 replication cycle regulation increasing the proviral transcription rate several hundred-fold and acting on the elongation of viral transcripts. Moreover, Tat displays several important biological activities committed to uninfected and infected cells by a paracrine/autocrine mechanism due to secretion of Tat from infected cells. In particular, Tat modulates the expression of several cellular genes and triggers the activation of some signal transduction pathways and transcription factors suggesting a complex role in the scenario of HIV-1 infection. This review focuses on some aspects of Tat biological activity with particular regard to effects of Tat on cell proliferation and survival regulation.
Topics: Animals; Apoptosis; Cell Line; Cell Proliferation; Cell Survival; Gene Expression Regulation; Gene Products, tat; HIV-1; Humans; Mice; Mice, Transgenic; Proteins; tat Gene Products, Human Immunodeficiency Virus
PubMed: 16035254
DOI: No ID Found -
Advanced Drug Delivery Reviews Feb 2005The direct intracellular delivery of proteins, or active peptide domains, has, until recently, been difficult to achieve due primarily to the bioavailability barrier of... (Review)
Review
The direct intracellular delivery of proteins, or active peptide domains, has, until recently, been difficult to achieve due primarily to the bioavailability barrier of the plasma membrane, which effectively prevents the uptake of macromolecules by limiting their passive entry. Traditional approaches to modulate protein function have largely relied on the serendipitous discovery of specific drugs and small molecules which could be delivered easily into the cell. However, the usefulness of these pharmacological agents is limited by their tissue distribution and unlike 'information-rich' macromolecules, they often suffer from poor target specificity, unwanted side-effects, and toxicity. Likewise, the development of molecular techniques, over the past several decades, for gene delivery and expression of proteins has provided for tremendous advances in our understanding of cellular processes but has been of surprisingly little benefit for the management of genetic disorders. Apart from these gains however, the transfer of genetic material into eukaryotic cells either using viral vectors or by non-viral mechanisms such as microinjection, electroporation, or chemical transfection remains problematic. Moreover, in vivo, gene therapy approaches relying on adenoviral vectors are associated with significant difficulties relating to a lack of target specificity and toxicity which have contributed to poor performance in several clinical trials. Remarkably, the recent identification of a particular group of proteins with enhanced ability to cross the plasma membrane in a receptor-independent fashion has led to the discovery of a class of protein domains with cell membrane penetrating properties. The fusion of these protein transduction domain peptide sequences with heterologous proteins is sufficient to cause their rapid transduction into a variety of different cells in a rapid, concentration-dependent manner. Moreover, this novel technique for protein and peptide delivery appears to circumvent many problems associated with DNA and drug based methods. This technique may represent the next paradigm in our ability to modulate cell function and offers a unique avenue for the treatment of disease.
Topics: Animals; Cell Membrane; Gene Products, tat; HIV-1; Humans; Neoplasms; Peptides; Protein Transport; Signal Transduction; Transduction, Genetic; tat Gene Products, Human Immunodeficiency Virus
PubMed: 15722165
DOI: 10.1016/j.addr.2004.10.005 -
Retrovirology May 2009The human immunodeficiency virus type 1 (HIV-1) trans-activator of transcription protein Tat is an important factor in viral pathogenesis. In addition to its function as... (Review)
Review
The human immunodeficiency virus type 1 (HIV-1) trans-activator of transcription protein Tat is an important factor in viral pathogenesis. In addition to its function as the key trans-activator of viral transcription, Tat is also secreted by the infected cell and taken up by neighboring cells where it has an effect both on infected and uninfected cells. In this review we will focus on the relationship between the structure of the Tat protein and its function as a secreted factor. To this end we will summarize some of the exogenous functions of Tat that have been implicated in HIV-1 pathogenesis and the impact of structural variations and viral subtype variants of Tat on those functions. Finally, since in some patients the presence of Tat-specific antibodies or CTL frequencies are associated with slow or non-progression to AIDS, we will also discuss the role of Tat as a potential vaccine candidate, the advances made in this field, and the importance of using a Tat protein capable of eliciting a protective or therapeutic immune response to viral challenge.
Topics: AIDS Vaccines; HIV-1; Humans; tat Gene Products, Human Immunodeficiency Virus
PubMed: 19467159
DOI: 10.1186/1742-4690-6-50 -
The New Microbiologica Apr 2001In the last few years, literature reports have unequivocally established that the 86-101 aminoacid Tat protein, essential for an efficient viral replication, can be... (Review)
Review
In the last few years, literature reports have unequivocally established that the 86-101 aminoacid Tat protein, essential for an efficient viral replication, can be actively secreted by infected cells. The contribution of extracellular Tat to the progression of viral infection is underlined by the ability of neutralizing anti Tat antibody to reduce the viral load in vitro and possibly also in vivo. Considering that at least some of the effect of Tat protein seem to be the consequence of an autocrine loop and that anti Tat antibody is an efficient inhibitor of viral replication, it is reasonable to suppose that extracellular Tat play a functional role in HIV-1 infection and that HIV antibody may interfere with a possible Tat driven pathogenesis. This review explores the meaning of anti Tat antibody in vitro and in vivo and its importance to shed more light on viral pathogenesis and the recent development of Tat containing vaccine.
Topics: AIDS Vaccines; Autocrine Communication; Gene Products, tat; HIV Antibodies; HIV Antigens; HIV Infections; HIV-1; Humans; tat Gene Products, Human Immunodeficiency Virus
PubMed: 11346305
DOI: No ID Found -
Journal of Virology Jul 2018Transcription of the HIV-1 proviral DNA and subsequent processing of the primary transcript results in the production of a large set of unspliced and differentially...
Transcription of the HIV-1 proviral DNA and subsequent processing of the primary transcript results in the production of a large set of unspliced and differentially spliced viral RNAs. The major splice donor site (5'ss) that is located in the untranslated leader of the HIV-1 transcript is used for the production of all spliced RNAs, and splicing at this site has to be tightly regulated to allow the balanced production of all viral RNAs and proteins. We demonstrate that the viral Tat protein, which is known to activate viral transcription, also stimulates splicing at the major 5'ss. As for the transcription effect, Tat requires the viral long terminal repeat promoter and the -acting responsive RNA hairpin for splicing regulation. These results indicate that HIV-1 transcription and splicing are tightly coupled processes through the coordinated action of the essential Tat protein. The HIV-1 proviral DNA encodes a single RNA transcript that is used as RNA genome and packaged into newly assembled virus particles. This full-length RNA is also used as mRNA for the production of structural and enzymatic proteins. Production of other essential viral proteins depends on alternative splicing of the primary transcript, which yields a large set of differentially spliced mRNAs. Optimal virus replication requires a balanced production of all viral RNAs, which means that the splicing process has to be strictly regulated. We show that the HIV-1 Tat protein, a factor that is well known for its transcription activating function, also stimulates splicing. Thus, Tat controls not only the level of the viral RNA but also the balance between spliced and unspliced RNAs.
Topics: Gene Expression Regulation, Viral; Gene Products, tat; HEK293 Cells; HIV Infections; HIV-1; Humans; RNA Splicing; RNA, Viral; Virus Replication
PubMed: 29743356
DOI: 10.1128/JVI.01855-17 -
Journal of Immunology (Baltimore, Md. :... Dec 2000Human basophils and mast cells express the chemokine receptor CCR3, which binds the chemokines eotaxin and RANTES. HIV-1 Tat protein is a potent chemoattractant for...
Human basophils and mast cells express the chemokine receptor CCR3, which binds the chemokines eotaxin and RANTES. HIV-1 Tat protein is a potent chemoattractant for basophils and lung mast cells obtained from healthy individuals seronegative for Abs to HIV-1 and HIV-2. Tat protein induced a rapid and transient Ca(2+) influx in basophils and mast cells, analogous to beta-chemokines. Tat protein neither induced histamine release from human basophils and mast cells nor increased IL-3-stimulated histamine secretion from basophils. The chemotactic activity of Tat protein was blocked by preincubation of FcepsilonRI(+) cells with anti-CCR3 Ab. Preincubation of Tat with a mAb anti-Tat (aa 1-86) blocked the migration induced by Tat. In contrast, a mAb specific for the basic region (aa 46-60) did not inhibit the chemotactic effect of Tat protein. Tat protein or eotaxin desensitized basophils to a subsequent challenge with the autologous or the heterologous stimulus. Preincubation of basophils with Tat protein up-regulated the level of CCR3 mRNA and the surface expression of the CCR3 receptor. Tat protein is the first identified HIV-1-encoded beta-chemokine homologue that influences the directional migration of human FcepsilonRI(+) cells and the expression of surface receptor CCR3 on these cells.
Topics: Adult; Antibodies, Monoclonal; Basophils; Calcium; Calcium Signaling; Cell Migration Inhibition; Cell Movement; Chemokine CCL11; Chemokines, CC; Chemotaxis, Leukocyte; Cytokines; Epitopes; Gene Expression Regulation; Gene Products, tat; HIV-1; Histamine Release; Humans; Lung; Mast Cells; RNA, Messenger; Receptors, CCR3; Receptors, Chemokine; Receptors, HIV; Receptors, IgE; Sequence Homology, Amino Acid; Up-Regulation; tat Gene Products, Human Immunodeficiency Virus
PubMed: 11120849
DOI: 10.4049/jimmunol.165.12.7171 -
Methods in Molecular Medicine 2005TAT protein transduction is a novel method of delivering biologically active proteins into cells and tissues through the fusion of a protein transduction domain to the... (Review)
Review
TAT protein transduction is a novel method of delivering biologically active proteins into cells and tissues through the fusion of a protein transduction domain to the protein of interest. The present chapter outlines the methodology pertaining to the preparation of TAT-fusion proteins and how to efficiently transduce these proteins into cultured cells or isolated rat hearts perfused in Langendorff mode.
Topics: Animals; Cells, Cultured; Escherichia coli; Gene Products, tat; Heart; Myocardium; Myocytes, Cardiac; Organ Culture Techniques; Perfusion; Protein Structure, Tertiary; Rats; Recombinant Fusion Proteins; Transduction, Genetic
PubMed: 16010012
DOI: No ID Found -
BMC Infectious Diseases Mar 2023HIV-1 remains a global health concern and to date, nearly 38 million people are living with HIV. The complexity of HIV-1 pathogenesis and its subsequent prevalence is... (Review)
Review
HIV-1 remains a global health concern and to date, nearly 38 million people are living with HIV. The complexity of HIV-1 pathogenesis and its subsequent prevalence is influenced by several factors including the HIV-1 subtype. HIV-1 subtype variation extends to sequence variation in the amino acids of the HIV-1 viral proteins. Of particular interest is the transactivation of transcription (Tat) protein due to its key function in viral transcription. The Tat protein predominantly functions by binding to the transactivation response (TAR) RNA element to activate HIV-1 transcriptional elongation. Subtype-specific Tat protein sequence variation influences Tat-TAR binding affinity. Despite several studies investigating Tat-TAR binding, it is not clear which regions of the Tat protein and/or individual Tat amino acid residues may contribute to TAR binding affinity. We, therefore, conducted a scoping review on studies investigating Tat-TAR binding. We aimed to synthesize the published data to determine (1) the regions of the Tat protein that may be involved in TAR binding, (2) key Tat amino acids involved in TAR binding and (3) if Tat subtype-specific variation influences TAR binding. A total of thirteen studies met our inclusion criteria and the key findings were that (1) both N-terminal and C-terminal amino acids outside the basic domain (47-59) may be important in increasing Tat-TAR binding affinity, (2) substitution of the amino acids Lysine and Arginine (47-59) resulted in a reduction in binding affinity to TAR, and (3) none of the included studies have investigated Tat subtype-specific substitutions and therefore no commentary could be made regarding which subtype may have a higher Tat-TAR binding affinity. Future studies investigating Tat-TAR binding should therefore use full-length Tat proteins and compare subtype-specific variations. Studies of such a nature may help explain why we see differential pathogenesis and prevalence when comparing HIV-1 subtypes.
Topics: Humans; HIV-1; tat Gene Products, Human Immunodeficiency Virus; HIV Long Terminal Repeat; Amino Acids; RNA, Viral
PubMed: 36932337
DOI: 10.1186/s12879-023-08123-0 -
Current Medicinal Chemistry 2006The transactivation responsive (TAR) RNA is the 5'-leader sequence of the HIV-1 mRNA genome and interacts with the Tat protein during transcription. Tat and the positive... (Review)
Review
The transactivation responsive (TAR) RNA is the 5'-leader sequence of the HIV-1 mRNA genome and interacts with the Tat protein during transcription. Tat and the positive transcription elongation factor (P-TEFb) complex bind to TAR to promote efficient transcription of the full-length HIV genome. In the absence of the TAR.Tat.P-TEFb interaction, viral transcription is inefficient, which makes this RNA-protein complex an important target for therapeutic intervention of HIV replication. Inhibitors of HIV-1 transactivation mainly target: 1) TAR RNA, 2) Tat protein and 3) Tat.P-TEFb complex. 1) Compounds against TAR RNA are the most numerous: besides cationic peptides, which were initially developed, recent advances in TAR binding inhibitors include oligonucleotide based-agents and small molecules. Specific research efforts are currently underway to increase cellular uptake. 2) By targeting the Tat protein, both transactivation and other Tat-mediated intra/extracellular functions are affected. Various biopolymeric drugs are reported to effectively inhibit Tat activity. In addition, Tat-targeted antibodies have recently been developed. 3) Intracellular proteins have been discovered to disrupt Tat.P-TEFb interaction, raising the chance of inhibiting HIV-1 transcription via novel mechanisms.
Topics: Anti-HIV Agents; Gene Products, tat; HIV Long Terminal Repeat; HIV-1; Humans; Molecular Structure; Positive Transcriptional Elongation Factor B; RNA, Viral; Transcriptional Activation; tat Gene Products, Human Immunodeficiency Virus
PubMed: 16712471
DOI: 10.2174/092986706776872989 -
Current Drug Targets. Immune, Endocrine... Dec 2004Transcription of the integrated HIV-1 proviral genome is an essential step in the retrovirus life cycle and thus an appealing target for chemotherapeutic intervention to... (Review)
Review
Transcription of the integrated HIV-1 proviral genome is an essential step in the retrovirus life cycle and thus an appealing target for chemotherapeutic intervention to restrict retroviral replication. A fundamental role in this process is exerted by the viral protein Tat, a powerful transactivator of viral gene expression. This protein binds a structured RNA sequence at the 5'-ends of all nascent viral mRNAs and promotes transcription by mediating the recruitment to the viral promoter of cellular factors required for chromatin remodelling and transcriptional processivity. In addition to these transcriptional activities, Tat is released from the cells and enters neighbouring cells when present in the extracellular environment, a process that is possibly involved in HIV disease pathogenesis. Given its pleiotropic functions, the protein represents a highly appealing target for drug development. Here I will summarise the known molecular mechanisms by which Tat exerts its activities and review the currently available compounds that interfere with the process of transcriptional activation of the HIV-1 provirus.
Topics: Amino Acid Sequence; Animals; Drug Delivery Systems; Gene Products, tat; HIV-1; Humans; Molecular Sequence Data; Protein Binding; tat Gene Products, Human Immunodeficiency Virus
PubMed: 15578978
DOI: 10.2174/1568008043339767