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Manipulating the Intracellular Trafficking of Nucleic Acids
Published in Kenneth L. Brigham, Gene Therapy for Diseases of the Lung, 2020
Kathleen E. B Meyer, Lisa S. Uyechi, Francis C. Szoka
The HIV-1 matrix protein (MA), whose function was originally identified in the assembly of the viral capsid, has been recognized as the nuclear targeting component of the HIV-1 preintegration complex (134,135). The viral preintegration complex consists of RNA, cDNA, integrase, reverse transcriptase, and MA protein. The 17-kDa MA protein contains a putative nuclear localizing sequence (NLS) conferring nuclear transport activity to the HIV-1 preintegration complex, when attached to a secondary transport receptor (136) (Fig. 7). A stretch of basic amino acids on the N-terminus of MA matches the four residue consensus sequence (K-R/K-X-R/K) identified from the SV40 class of NLS (120). Mutations in this N-terminal region prevent replication of HIV-1 in nondividing cells (120), confirming the role of the native NLS sequence in nuclear transport. Some HIV-1 strains also contain an auxiliary gene product, vpr, which is a redundant nuclear localizing protein and confers increased karyophilicity of the preintegration complex (137). Although a localization signal sequence has not been identified on vpr, an atypical one is suspected (135,136). Another protein that may serve a nuclear transport function is Tat, which has a nuclear localization signal sequence in addition to an RNAbinding domain (138). Transport of the HIV-1 pre-integration complex is ATP-dependent, inhibited by wheat germ agglutinin, and attenuated by competing with SV40 large T NLS or HIV MA (139). These results are consistent with a nuclear pore-mediated mechanism of entry.
Bacillus
Published in Dongyou Liu, Laboratory Models for Foodborne Infections, 2017
Jessica Minnaard, Ivanna S. Rolny, Pablo F. Pérez
Early studies used this model to analyze crude cell-free spent culture supernatants of B. cereus cultures.170 Biological activity was detected through two main experimental approaches: accumulation of fluid in ligated rabbit ileal loops (RILs) and vascular permeability reaction (VPR). In the RIL test, samples are injected into ileal loops and fluid accumulation is evaluated after euthanasia. Results obtained with this technique correlated with those obtained in the VPR. This latter assay involves the intradermal injection of samples in the shaved back of rabbits. Next, a Blue Evans solution is administered intravenously (ear vein), and the diameter of blue zones in the inoculation zone is evaluated. In some cases, edema and hemorrhage are also present.170 It has been suggested that capillaries of blood were affected by B. cereus enterotoxin, giving a local and also a systemic response since histological changes were observed in the liver.171 Comparing with ligated ileal loop assays, the VPR is faster, cheaper, and easier to perform.172
Human Immunodeficiency Virus Neuropathogenesis
Published in Sunit K. Singh, Daniel Růžek, Neuroviral Infections, 2013
Vpr is a 96-amino acid HIV-1-encoded virion-incorporated protein and essential for HIV-1 replication in macrophages (Subbramanian et al. 1998). Vpr has been recently reported in sustantial amounts in both the basal ganglia and the frontal cortex of HIVE patients. It was mainly found in the resident macrophages and neurons (Wheeler et al. 2006). Soluble HIV-1 Vpr protein is reported in the serum of HIV-infected patients with neurological disorders (Levy et al. 1994). In the mouse model, the expression of HIV-1 Vpr in brain monocytoid cells has been implicated in neuronal injury and other motor dysfunctions (Jones et al. 2007). Exogenous treatment of soluble Vpr also perturbs the neuronal membrane potentials, leading to apoptosis (Patel et al. 2000). Vpr directly exert cytotoxic effects on neurons by activating the glia, which results into the release of neurotoxic substances. Vpr can also alter the expression of various important cytokines and inflammatory proteins in infected as well as uninfected cells (Mukerjee et al. 2011). Vpr is known to be taken up by neurons and leads to the deregulation of calcium homeostasis. Vpr can also activate the oxidative stress pathway involving mitochondrial dysfunction (Mukerjee et al. 2011).
Gynura procumbens ethanol extract improves vascular dysfunction by suppressing inflammation in postmenopausal rats fed a high-fat diet
Published in Pharmaceutical Biology, 2021
Khuzaidatul Azidah Ahmad Nazri, Qodriyah Haji Mohd Saad, Norsyahida Mohd Fauzi, Fhataheya Buang, Ibrahim Jantan, Zakiah Jubri
The systolic blood pressure (SBP) was measured using a non-invasive tail-cuff method (CODA Powerlab, AD Instruments, NSW, Australia) at the interval of 3 months treatment period for 6 months (Adam et al. 2009). This system uses volume pressure recording (VPR) by considering the changes of volumes occurring in the tail to measure the SBP. Briefly, the rats were pre- warmed under sunlight for 10 min to adapt to the environment before measuring the SBP. Concurrently, a strainer tube was swabbed with 70% ethanol, and the CODA system was calibrated according to the standard settings recommended by the manufacturer. A rat was placed in the strainer tube where its tail was adjusted in a comfortable position to prevent excessive movement of the occlusion cuff near the proximal end of the strainer tube. Five valid readings of SBP were taken, and the mean of SBP was calculated for each rat.
Important role of microglia in HIV-1 associated neurocognitive disorders and the molecular pathways implicated in its pathogenesis
Published in Annals of Medicine, 2021
A. Borrajo, C. Spuch, M. A. Penedo, J. M. Olivares, R. C. Agís-Balboa
Direct HIV-mediated neurotoxicity is related to the interaction between neurons and viral proteins gp120, viral surface glycoprotein 41 (gp41), negative regulatory factor (Nef), Tat, Vpr, and Viral protein U (Vpu), resulting in neuronal injury or apoptosis and contributing to CNS pathology (Figure 1) [76]. During the process of HIV entry into host cells, the viral envelope proteins gp120 and gp41 may damage other neurons in close proximity to them. More of these damaging viral proteins are released when viral replication is high leading to the release of viral particles from these infected cells [77] through a direct mechanism involving the induction of ROS production and increased cell death [78–81]. Elevated levels of ROS increases DNA nucleic acid oxidation, causing DNA instability, and also inhibits DNA repair by eliminating DNA glycosylase 1 [82]. Gp120 and Tat further contribute to neurotoxicity by increasing lipid peroxidation, leading to the accumulation of ceramide [83]. Vpr protein provokes G2/M arrest and plays a role in the infection of macrophages [84], HIV transcription, and apoptosis [85,86]. Finally, Vpu induces virion release by preventing the action of host restriction factors [87,88], downregulating CD4 during the late stages of HIV-1 infection [89], and impeding Nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-κB) activation [89,90].
Macrophage targeted nanocarrier delivery systems in HIV therapeutics
Published in Expert Opinion on Drug Delivery, 2020
Tabassum Khan, Mayuresh Mayuresh Patkar, Munira Momin, Abdelwahab Omri
VPR is a virion-associated protein vital for replication in macrophages and T cells and is localized in nucleus and cytoplasm of the infected cells [30–32]. It transactivates the HIV-1 long-terminal repeat (LTR) and viral promoter which increases the replication of virions. Recombinant VPR (rVPR) triggers HIV-1 replication in acutely infected primary macrophages [33,34]. Thus, VPR enhances the viral replication in acutely infested macrophages [23]. Additionally, VPR is known to interact with cellular protein DCAF1 (VprBP) and counteract antiviral restriction in infected macrophages. This interaction helps HIV to spread the infection from macrophages to CD4+ T cells. VPR requires DCAF1 to promote infected MDM to T lymphocyte spread of HIV infection [35]. DCAF1 is also essential virion production and evasion of IFN-mediated immune response. DCAF1 silencing inhibits HIV1 transmission from MDM to CD4+ T lymphocytes through downstream VPR blockade. This explains CD4+ T cells as the hosts for latent infection reservoir site along with macrophages.