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Walter M Chesnut

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1) ON THE STAGE 4 CANCER AUTOBAHN:THE GRP78 BRIDGE BETWEEN TUMOR MICROENVIRONMENT AND NEURODEGENERATION

One little-discussed, but, in my opinion, extremely importantinteraction of the Spike Protein is with GRP78. GRP78 can form a complex with SARS-2-S and ACE2on the

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2) surface and at the perinuclear region typical of the endoplasmic reticulum in VeroE6-ACE2 cells and that the substrate-binding domain of GRP78 is critical for this interaction.

What does this mean?

Endoplasmic-reticulum-associated protein degradation (ERAD) machinery in

3) combination with the ubiquitin-proteosome system (UPS) is thought to be the mechanism for quality control in long-lived cells such as neurons; hence, GRP78 is likely a critical component of the endogenous neuroprotective program.

The Spike BINDS to this, de facto impeding its

4) functionality. GRP78 plays a role in autophagic protein quality control, participating in the destruction of misfolded proteins in the cytosol. Therefore we can now observe acausal link to the appearance of neurodegenerative conditions.

Regarding cancer, GRP78 is involvedin

5)several aspects of cancer development including tumor survival and proliferation, chemoresistance, angiogenesis, and metastasis. Many tumor cells overexpress GRP78 on the outer plasma membrane. GRP78 can then be released into the bloodstream.

Indeed, high levels of GRP78 are

6) present in those with COVID.

GRP78 is also instrumental in tumorigenesis. A referenced study suggested that GRP78va has the potential to influence survival of cancer cells in adaptation to ER stress through modulating UPR signaling.

Stop. It. Now. Especially before the very

7) young are potentially affected.

frontiersin.org/articles/10.33…

ncbi.nlm.nih.gov/labs/pmc/artic…

jbc.org/article/S0021-…

Front. Immunol., 15 December 2020 | https://doi.org/10.3389/fimmu.2020.596631

Sharing CD4+ T Cell Loss: When COVID-19 and HIV Collide on Immune System

Xiaorong Peng1,2,3, Jing Ouyang4, Stéphane Isnard1,2,5, John Lin1,2, Brandon Fombuena1,2, Biao Zhu3 and Jean-Pierre Routy1,2,6*

https://www.frontiersin.org/articles/10.3389/fimmu.2020.596631/full

Conclusion

Both HIV-1 and SARS-CoV-2 infection share CD4+ T cell loss in association with disease outcome and immunodeficiency. Direct attacks on CD4+ T cells, immune activation and redistribution of CD4+ T cell are contributing mechanisms in very different proportion for CD4+ T cell lymphopenia in both diseases. During the period of immunodeficiency, systemic inflammation could be fueled by leaky gut and lead to severe complications. However, when HIV meets COVID-19, no increase in the occurrence of COVID-19 and no excess morbidity and mortality among PLWH with symptomatic COVID-19 has been reported. IL-7 and IL-2 were previously used to increase CD4+ T cell counts in HIV-1 infection, however, no improvement in their function were reported. Despite this, the short-term effect for COVID-19 is under investigation. As CD4+ T cells orchestrate immune responses, proper CD4+ T cell function is required for effective vaccine responses. Hence, anti-SARS-CoV-2 antibodies and CD4 responses should be studied in order to develop long-term efficiency vaccine formulation. Overall, experience in HIV clinical management and past clinical trials represent a special use case for innovative studies aiming at increasing CD4+ T cell function and reducing COVID-19 morbidity.

Funding

This work was funded by the China Scholarship Council (No.201906325018), the Canadian Institutes of Health Research (CIHR; grants MOP 103230 and PTJ 166049), the Vaccines & Immunotherapy Core of the CIHR Canadian HIV Trials Network (CTN, grant CTN 257), the CIHR-funded Canadian HIV Cure Enterprise (CanCURE) Team Grant HB2-164064, This work was also supported by the Fonds de la Recherche Québec-Santé (FRQ-S): Réseau SIDA/Maladies infectieuses and Thérapie cellulaire. JO is supported by the Chinese National Science and Technology Major Project during the 13th Five-Year Plan (No. 2018ZX10302104). SI is supported by a Fond de Recherche Québec Santé fellowship and a CIHR/CTN Postdoctoral Fellowship Award. JP-R is the holder of the Louis Lowenstein Chair in Hematology and Oncology, McGill University and William Turner award holder from the McGill University Health Centre.

https://www.frontiersin.org/articles/10.3389/fimmu.2020.596631/full

>>15599395

Introduction

An outbreak of an unknown infectious pneumonia occurred in Wuhan, China, in December 2019 (1). The pathogen of the disease was quickly identified as a novel coronavirus coined severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the disease was named coronavirus disease-19 (COVID-19) by the WHO (2–4). The virus has since caused more than 48 million confirmed cases and over 1.2 million deaths worldwide by November, 2020 (5). The majority of individuals with COVID-19 have mild clinical presentation with or without flu-like symptoms including dry cough, fever, a runny nose, fatigue, muscle pain and diarrhea. Some cases can evolve into acute respiratory distress syndrome, septic shock, coagulation dysfunction, and multiorgan failure (1, 6, 7). The severity of the disease is influenced by factors such as older age, obesity and metabolic syndrome (8, 9). Acute infection with SARS-CoV-2 is associated with lymphopenia in approximately 80% of patients (6, 10–21). Furthermore, lymphopenia with the suppression of B, helper (CD4+) and cytotoxic (CD8+) T cell function, is an indicator of a poor clinical outcome (10–15, 17–19, 21–27). It is likely that lymphopenia delays viral clearance, favoring macrophage stimulation and the accompanying cytokine storm, leading to organ dysfunction (7, 15, 18, 19, 21, 23, 24, 26, 28, 29).

Apart from SARS-CoV-2, other viruses—including SARS coronavirus, measles virus, avian influenza virus H5N1, swine foot-and-mouth disease virus, respiratory syncytial virus and human immunodeficiency virus (HIV)—are associated with lymphopenia (30). Among them, HIV can cause an well-known lymphopenia-associated disease acquired immune deficiency syndrome (AIDS) (31). The acute phase of HIV infection is characterized by a substantial drop in peripheral CD4+ T cell counts, while during the chronic phase, a slower and persistent decline of these CD4+ T cells is associated with the development of AIDS. Antiretroviral therapy (ART) rapidly suppresses HIV replication, and the number of CD4+ T cell counts recovers, preventing AIDS. However, systemic immune activation persists in those people even after years of ART (32), and is characterized by increased proinflammatory mediators and low CD4/CD8 ratio (33), combined with exhausted and senescent T cells. Systemic immune activation is also associated with non-infectious comorbidities, such as cardiovascular diseases, neurocognitive disorders and cancers.

pt 1 of intro

>>15599398

CD4+ T cells orchestrate the response to acute and chronic viral infections by coordinating the immune system. These cells activate multiple cells of the innate immune system, as well as B cells, cytotoxic CD8+ T cells, and non-immune cells. CD4+ T cells also play a key role for the establishment of long-term cellular and humoral antigen specific immunity, which is the basis of life-long protection for many viral infections and vaccines (34, 35).

Both HIV-1 and SARS-CoV-2 have distinct virological characteristics while sharing CD4+ T cell lymphopenia. In this review, we critically assessed the possible mechanisms and the potential influence of CD4+ T cell lymphopenia in acute and chronic viral infections. We also discuss host characteristics and hyper-inflammatory response in these two dramatic viral infections and the impact of COVID-19 infection in people living with HIV (PLWH).

pt 2 of 2 of intro

>>15599404

as you know it. consider it correctly as sorcery and weapons, and it is as real as any other agent in substance. manipulation of micro to affect macro. But BY DESIGN