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Packaging of DNA into chromatin adds complexity to the problem of regulation of gene expression. Nucleosomes affect the accessibility of transcription factors to occupy their binding sites in chromatin of eukaryotic cells. The disruption of nucleosome structure within the enhancer/promoter region of the integrated HIV-1 proviral genome is an instructive example of a chromatin remodeling process during transcriptional activation. To investigate the mechanism responsible for generating nuclease hypersensitive sites that exist in vivo in the promoter/enhancer region of the 5'LTR (long terminal repeat) of integrated HIV-1 we have utilized an in vitro chromatin assembly system with Xenopus oocyte extracts. Chromatin assembly in the presence of Sp1 and NFκB transcription factors induces DNase I hypersensitive sites on either side of their binding sites and positions the adjacent nucleosomes. This structure can also be formed in a factor-induced, ATP-dependent chromatin remodeling process and closely resembles the in vivo chromatin structure. The DNase I hypersensitive sites that form within the HIV LTR are probably histone-free and remain after removal of transcription factors.
The analysis of the history of the research on antivirals especially the treatment of III V-l-infected individuals with antivirals which were developed prior to the current AIDS epidemic led to suggest a different approach to the targeting of antivirals in the AIDS patients. Since HIV-1 replication in infected individuals occurs in the lymph nodes, it is suggested that modified anti-Hl V-l drugs should be applied to Langerhans cells in the skin. The Langerhans cells can serve as the carries of the antiviral drugs attached to their surfaces due to their ability to migrate from the skin through the lymph vessels and to home to the lymph node. At that site Langerhans cells interact with T cells. Transfer of the anti-HIV-1 drugs to infected CD4+ T cells in the lymph node will reduce virus replication in the lymph nodes and will reduce the cytotoxic systemic effects of the antiviral drug. Such an antiviral treatment requires the development of efficient methods of drug delivery through the skin.
HIV-1 or Human Immuno Deficiency Virus-1 is the main causative agent of Acquired Immuno Deficiency Syndrome (AIDS). Human host infected with HIV - 1 extensively harbours many viral variants but very little is known about the difference in pattern[17] of evolution of phylogenetic lineages of HIV-1 non recombinant, normal inter subtype recombinant and main two specific recombinant forms of HIV-1 i.e., Circulating Recombinant Forms (CRFs) and Unique Recombinant Forms (URFs). This study is mainly concerned with study of the difference in evolutionary lineages of non-recombinant and recombinant sequences of HIV-1 genome sequences and identification of geographically rich areas which has reported high degree of HIV-1 occurrence and variety. Total 1550 HIV-1 genome sequences were obtained from HIV Los Alamos Database. The sequences were aligned using MAFFT (Multiple Alignment using Fast Fourier Transform) web server tool. Alignment was carried out using 10 different set of alignment parameter values. After alignment the aligned file was used for constructing N-J phylogenetic tree using Clustal X2 tool. Phylogenetic analysis was performed keeping in mind the category to which the sequence belongs. Upon analysis it was observed that the clade containing the probable ancestor belongs remained constant in all cases of different alignment values. Non recombinant isolates, inter subtype recombinants, CRFs, URFs all followed different patterns of evolution. Non recombinant sequences were found geographically specific and subtype specific to some extent whereas, normal recombinants were subtype specific and less geographically specific. CRFs showed variation among the pattern of their evolution. At some instances the sequences occurred as sister taxa of non-recombinant or normal inter subtype recombinant sequences, while at some instances as sister taxa of other CRFs where they were geographically specific. Three CRFs existed as completely diverged sequences. URFs were four in number; two of them were Indian isolates of while other two were Japanese isolates. URFs were found to be totally geographically specific. Geography wise high rate of variation was observed in India and Japan as these two countries had sequences belonging to all of the above categories. Cameroon and South Africa have very large number isolates and a considerable amount of genetic variation among isolates but they lack URFs.
The proteasome is a main protease of the ubiquitin-proteasome pathway, responsible for degradation of the majority of intracellular proteins in human cells. Since the proteasome regulates so many processes, abnormalities in its functioning play a causal role in a number of diseases, including muscular dystrophy, cardiovascular diseases and various cancers. The ubiquitin-proteasome pathway is involved also in disorders affecting central nervous system – cerebral ischemia/reperfusion injury and stroke. This implication in pathological condition makes the proteasome an important and very promising therapeutic target. The 26S proteasome, which is responsible for ATP-dependent proteolysis of ubiquitin-tagged proteins, consists of a barrel-like core particle – the 20S proteasome, and attached to it two regulatory particles 19S. The core particle is composed of four rings (αββα). The inner β-rings harbour active sites, which display distinct specificities and are responsible for cleavages of polypeptides after hydrophobic, acidic and basic residues (Marques et al. 2009). On the other hand, N-terminal residues of α subunits create a gate leading to the catalytic chamber. Because most of the already known proteasome inhibitors are competitive they are not selective enough and can block all active sites causing cell apoptosis. We believe that allosteric modulators may be an interesting alternative to active site inhibitors. The multi-subunit and multi-active sites structure of the proteasome creates an opportunity to selective allosteric regulation of its activity. We focus our searching on biomolecules which bind to the α-ring of the 20S proteasome and influence the enzyme’s gating mechanism. HIV-1 Tat protein is one of the natural proteasome regulators competing with 11S activator for binding to the α-rings (Huang et al. 2002). We designed two peptides: G48RKKRRQRRRPS59 (Tat1) and R49KKRRQRR56Q66DPI69 (Tat2) based on a sequence of the basic domain of the protein (Jankowska et al. 2010). We found that both of them efficiently inhibit 20S proteasome. We tried to connect the biological activity of Tat peptides to their structure determined by means of CD, FTIR, NMR and molecular dynamics simulation. Additionally, we synthesized alanine scan of Tat2 to determine the importance of individual amino acids. We exchanged not only single residues but also several adjacent amino acids at once and tested the influence of these changes on the proteasome activity. We also investigated the scan peptides’ structure using FTIR. The work was supported by grants: 538-8440-1043-12, DS/8440-4- 0172-2 and NCN 2011/01/B/ST5/06616
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