China
Africa
Explore chapters and articles related to this topic
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.
The Acquired Immunodeficiency Syndrome (AIDS)
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
The vif gene product facilitates virus release and increases viral particle infectivity. It may act as a cysteine protease on the Env protein. Vpu facilitates budding of the virus. This protein is not a component of the mature virion, but the ability of HIV to infect other cells depends on its activity. The vpr gene product is contained in virus particles. This molecule enhances viral replication, but the mechanism is unknown.
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).
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.
Nanocarriers for brain specific delivery of anti-retro viral drugs: challenges and achievements
Published in Journal of Drug Targeting, 2018
Nila Mary Varghese, Venkatachalam Senthil, Shailendra K. Saxena
The neuropathogenesis of neuroAIDS is primarily defined by HIV neurotropism, effects of cytokine production and viral proteins, and immune response (Figure 2) [12]. Most prominent neurodegenerative changes are observed in the basal ganglia, brainstem and deep white matter of the CNS. The monocytes/macrophages that get activated through HIV entry, secretes cytokines (tumor necrosis factor (TNF)-alpha and interleukin-1 beta) and chemokines, which together with the HIV-encoded proteins [glycoprotein 120 (gp120), viral protein R (Vpr) and TAT] produces cytotoxic effects on neurons, astrocytes or Schwann cells. This ultimately reduces the viability and survival of neural cells through neural process retraction [13]. The activated macrophages/monocytes also modifies the permeability of BBB, by getting adhered to the endothelial membrane of the BBB and triggering an array of harmful processes whereby the integrity of BBB is lost, and hence promotes the entry of more infected immune cells and free virus to the CNS. The viral proteins gp120 and trans-activator of transcription (TAT) are by themselves neurotoxic in nature, where they stimulate the production of more cytokine and eventually increases the permeability of BBB. Together with, they cause production of free radicals and oxidative stress, which when combined with activation of inflammatory process play an important role in pathogenesis of neuroAIDS [14–18]. The gp120 protein also causes neuronal apoptosis by direct interaction with the N-methyl-d-aspartate receptor or, indirectly, by the production of TNF by non-neuronal cells. Another viral protein, Vpr, induces cell cycle arrest and causes neuronal cell death through a caspase-8-dependent mechanism [19,20]. The formation of microglial nodules and multinucleated giant cells of myeloid lineage serves as the major reservoir of HIV in the CNS that can further reinfect the peripheral cells in the later stages of infection [21]. Though cART is able to quantitatively reduce the viral particlesin the body of an infected patient to an undetectable level, the poor permeability and bioavailability of ARVs to the brain provides a complete shelter for the viral particles to reside in the brain, thus aggravating neuroAIDS.