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Host-Directed and Immune-Based Therapies for Human Immunodeficiency Virus Infection
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
Hernan Valdez, Michael M. Lederman, Bharat Ramratnam, Timothy P. Flanigan
Administration of autologous expanded CD8+ lymphocytes has not resulted in the demonstration of any immunological or virological benefit that could not be attributed to coadministration of interleukin 2 (discussed below) [29]. Human immunodeficiency virus 1-specific cytotoxic T lymphocyte CTL are a predictable response to infection, and the nature and magnitude of the CTL response may be important predictors of outcome of HIV-1 infection (reviewed in Ref. 30). A single subject trial of ex vivo expansion and periodic reinfusion of a Nef-specific CTL clone has been reported [31]. In this study, there was no clinical benefit of the treatment; however, sequencing of virus isolated after several infusions revealed that approximately one quarter of the isolates now contained mutations in the Nef peptide targeted by the CTL clone, suggesting that infusion of these cells exerted a selection pressure (antiviral effect). Trials of ex vivo HIV-specific CTL expansions and reinfusions are ongoing [32]. It remains to be seen whether oligoclonal expansions will produce antiviral activities less susceptible to viral escape.
The Acquired Immunodeficiency Syndrome (AIDS)
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
The Nef (negative factor) protein has GTPase activity and may interfere with intracellular signalling in infected cells. Nef is detected soon after infection, before other mRNAs, including those encoding Tat and Rev. Nef may inhibit early replication steps (down-regulates transcription) and promote latency. Little is known concerning its role in viral replication. Nef is not required for HIV replication.
Recent Advances In HIV/AIDS
Published in Anne George, K. S. Joshy, Mathew Sebastian, Oluwatobi Samuel Oluwafemi, Sabu Thomas, Holistic Approaches to Infectious Diseases, 2017
It is very much clear that NEF plays critical role in AIDS pathogenesis. The nef is known to prevent the death of infected cells, contributing to increased viral load. The mechanism involves prevention of apoptosis of infected cells by either inhibiting proteins involved in apoptosis or preventing the infected cells from being recognized by Cytotoxic T Lymphocytes. Neutralization of nef can hasten the death of infected cells and help reduce the viral load. Nef is therefore a very important molecular target for developing therapeutics that slows disease progression to AIDS. The N-terminal region of nef and the naturally occurring bee venom mellitin have very similar primary and tertiary structures, and they both act by destroying membranes. Chemical analogs of a mellitin inhibitor prevent nef-mediated cell death and inhibit the interaction of NEF with cellular proteins involved in apoptosis. Naturally occurring bee propolis also contains substances that prevent nef-mediated cell lysis and increases proliferation of CD4 cells in HIV-infected cultures. These chemical compounds and natural products are water soluble and nontoxic and are therefore can be used as potential drugs (Ahmed, 2005).
Cellular Calcium Signals in Cancer Chemoprevention and Chemotherapy by Phytochemicals
Published in Nutrition and Cancer, 2022
Xue Li, Shuhan Miao, Feng Li, Fen Ye, Guang Yue, Rongzhu Lu, Haijun Shen, Yang Ye
NEF is a natural alkaloid compound found in lotus seed in Nelumbo nucifera, a traditional Chinese medicine (137). NEF shows a variety of pharmacological actions, such as anti-hypertensive, anti-diabetic, cardioprotection, neuroprotection, nephroprotection, anticancer and chemosensitizing effects (138). Several studies have shown that NEF exerts anticancer effects through ROS generation (139, 140), activation of the MAPK pathway (141, 142), microRNAs (143), the PI3K-AKT signaling pathway, autophagy (144) and cell cycle arrest (145). Law et al. reported that the chemotherapeutic efficacy of NEF via the modulation of calcium signals has been studied in apoptosis-resistant cancer cells. In addition, NEF activates RyRs to release cytoplasmic Ca2+, followed by activation of the calcium-dependent kinase β CaMKKβ, Ulk-1-PERK and AMPK-mTOR signaling pathways and induction of autophagy-dependent cell death in apoptosis-resistant cancers (146). In addition, NEF has been reported to raise cytosolic Ca2+ levels in A549 lung cancer cells through the rapid influx of Mn2+, thereby disrupting mitochondrial function (145). Furthermore, Ca2+-dependent ER stress and cell cycle arrest were enhanced by treatment with NEF (147). Taken together, these studies suggested that targeting calcium signaling regulators to enhance cancer cell death could be a new therapeutic strategy for cancer treatment.
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
NEF, a 27 kDa myristoylated protein, expressed at initial stages in the life cycle of HIV, is vital for viral replication in infected cells [35,36]. It improves the survival of infected cells that assists in viral population. It blocks immune system via mechanisms like activation of phosphoinositide-3 kinase (PI3K) [37,38] and downregulation CD28, MHC I, and MHC II [38,39]. Within macrophages, NEF expression induces secretion of soluble CD23 and ICAM via adenoviral vectors which results in up-regulation of costimulatory B cell receptors. T cell activation occurs due to the interaction with B cells which generates infected T cell as latent infection reservoir site. NEF also downregulates the expression of CD4 receptors in macrophages that causes the release of viral progeny by avoiding sequestration of viral envelope by CD4 and superinfection which may cause premature cell death [23].
Extracellular vesicles and chronic inflammation during HIV infection
Published in Journal of Extracellular Vesicles, 2019
Paula Soledad Pérez, María Albertina Romaniuk, Gabriel A. Duette, Zezhou Zhao, Yiyao Huang, Lorena Martin-Jaular, Kenneth W Witwer, Clotilde Théry, Matías Ostrowski
As stated above, the viral protein Nef from both human and simian immunodeficiency virus has been reported to be incorporated into EVs [89,105,113]. Moreover, almost all Nef in the plasma of HIV patients was found to be associated with CD45+ EVs [114]. Interestingly, Nef-containing EVs were found even in the plasma of HIV-infected individuals under antiretroviral therapy and with undetectable viral loads [100,114]. The main effect reported for Nef+ EVs on recipient cells has been the promotion of apoptosis in primary CD4 + T cells [89] and cell lines [114], which could contribute to CD4 + T cell depletion. Moreover, as described above, Nef+ EVs promote TNF-α release by recipient cells [111]. It should be noted, though, that some have questioned EV incorporation of Nef [115], indicating that further studies may be required.