2003. The ADE of virus infection is a phenomenon in which virus-specific antibodies enhance the entry of virus, and in some cases the replication of virus, into monocytes/macrophages and granulocytic cells through interaction with Fc and/or complement receptors. This phenomenon has been reported in vitro and in vivo for viruses representing numerous families and genera of public health and veterinary importance. These viruses share some common features such as preferential replication in macrophages, ability to establish persistence and antigenic diversity. For some viruses, ADE of infection has become a great concern to disease control by vaccination.
Consequently numerous approaches have been made to the development of vaccines with minimum or no risk for ADE. Identification of viral epitopes associated with ADE or neutralization is important for this purpose. In addition clear understanding of the cellular events after virus entry through ADE has become crucial for developing efficient intervention. However the mechanisms of ADE still remain to be better understood. https://www.ncbi.nlm.nih.gov/pubmed/12725690
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Sars-Cov-2’s affinity for the ACE2 receptor is somewhere between 10 and 20 times higher than SARS, and it also creates viral loads thousands of times higher than SARS. These two characteristics point towards COVID-19 using antibody-dependent enhancement, or ADE, to enter human cells. This is when the virus is able to hijack white blood cells to more easily enter into the rest of our body's cells, allowing it to seep deep into its hosts' nervous systems, creating permanent neurological damage in the hosts it doesn't kill outright. …
Curiously Zhengli Shi, of U North Carolina and Wuhan fame, co-authored a 2019 paper which used inert viral shells to figure out exactly how SARS, with its affinity to the ACE2 receptor just like COVID-19, was able to harness ADE to hijack white blood cells for enhanced cell entry. A gain-of-function extension of this research would be exactly the kind of experiment that could've given birth to COVID-19, especially considering that 2019 paper managed to fine-tune the exact concentration of antibodies that would best facilitate ADE.
Both HIV and Dengue fever use antibody-dependent enhancement to boost their virulence, however its generally a phenomenon that takes a long time to occur when it happens in nature….Sars-Cov-2 also appears immediately to be able to enter its hosts nervous systems, killing many of its victims by attacking the region of the brain that controls breathing, drastically lowering white blood cell counts early on in infections and apparently re-infecting individuals who had already appeared to clear their infection….Additionally an unnaturally juiced-up ability to use ADE would also explain what other front-line medical workers are observing in their patients: "I'm seeing people who look relatively healthy with a minimal health history, and they are completely wiped out like they've been hit by a truck. This is knocking out what should be perfectly fit, healthy people. Patients will be on minimal support, on a little bit of oxygen, and then all of a sudden they go into complete respiratory arrest, shut down and can't breathe at all. That seems to be what happens to a lot of these patients: they suddenly become unresponsive or go into respiratory failure." … So this high lethality may be due in part to the multiple variants that had time to circulate in Wuhan, a hallmark of ADE since each subsequent variant is able to escape detection by our immune systems while still hijacking our white blood cells to increase its virulence.
http://www.softpanorama.org/Skeptics/Political_skeptic/Propaganda/Fear_as_propaganda_tool/Covid19/bioweapon_angle.shtml#Emergence_of_gain_of_function_bio_experiments
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Molecular Mechanism for Antibody-Dependent Enhancement of Coronavirus Entry 12-05-2019
However, detailed molecular mechanisms for ADE of coronavirus entry are still unknown. We previously discovered a monoclonal antibody (MAb) (named Mersmab1) which has strong binding affinity for MERS-CoV RBD and efficiently neutralizes MERS-CoV entry by outcompeting DPP4 (48); this discovery allowed us to comparatively study the molecular mechanisms for antibody-dependent and receptor-dependent viral entries.
In this study we examined how Mersmab1 binds to MERS-CoV spike, triggers the spike to undergo conformational changes and mediates viral entry into Fc receptor-expressing cells. We also investigated the pathways and antibody dosages for Mersmab1-dependent and DPP4-dependent viral entries. Our study sheds lights on the mechanisms of ADE and provides insight into vaccine design and antibody-based antiviral drug therapy......
Next we investigated whether Mersmab1 mediates MERS-CoV entry into Fc receptor-expressing cells. To this end we performed a MERS-CoV pseudovirus entry assay in which retroviruses pseudotyped with MERS-CoV spike (i.e., MERS-CoV pseudoviruses) were used to enter human cells expressing CD32A on their surface. The main advantage of pseudovirus entry assay is to focus on the viral entry step (which is mediated by MERS-CoV spike) by separating viral entry from the other steps of viral infection cycles (e.g., replication, packaging and release)....
To understand the pathways of Mersmab1-dependent MERS-CoV entry we evaluated the potential impact of different proteases on MERS-CoV pseudovirus entry; these proteases are distributed along the viral entry pathway. First, proprotein convertase inhibitor (PPCi) was used for examining the role of proprotein convertases in the maturation of MERS-CoV spike and the impact of proprotein convertases on the ensuing Mersmab1-dependent viral entry (Fig. 5A). The results showed that when MERS-CoV pseudoviruses were produced from HEK293T cells in the presence of PPCi, the cleavage of MERS-CoV spike by proprotein convertases was significantly inhibited (Fig. 5B). In the presence of Mersmab1, MERS-CoV pseudoviruses packaged in the presence of PPCi entered CD32A-expressing cells more efficiently than those packaged in the absence of PPCi (Fig. 5A)....
DISCUSSION ADE of viral entry has been observed and studied extensively in flaviviruses, particularly dengue virus (3–6). It has also been observed in HIV and Ebola viruses (7–10). For these viruses it has been proposed that primary viral infections of hosts led to production of antibodies that are subneutralizing or nonneutralizing for secondary viral infections; these antibodies cannot completely neutralize secondary viral infections but instead guide virus particles to enter Fc receptor-expressing cells. ADE can lead to worsened symptoms in secondary viral infections, causing major concerns for epidemiology. ADE is also a major concern for vaccine design and antibody-based drug therapy, since antibodies generated or used in these procedures may lead to ADE. ADE has been observed in coronaviruses for decades, but the molecular mechanisms are unknown. Recent advances in understanding of the receptor recognition and cell entry mechanisms of coronaviruses have allowed us to use coronaviruses as a model system for studying ADE....
Taken together our results show that RBD-specific neutralizing MAbs bind to the same region on coronavirus spikes as viral receptors do, trigger conformational changes of the spikes as viral receptors do, and mediate ADE through the same pathways as viral-receptor-dependent viral entry. In other words RBD-specific neutralizing MAbs mediate ADE of coronavirus entry by functionally mimicking viral receptors....
Finally, we analyzed ADE of coronavirus entry at different antibody dosages. MERS-CoV entry into cells expressing both viral and Fc receptors demonstrates complex MAb-dosage-dependent patterns. As the concentration of MAb increases, (i) viral entry into DPP4-expressing cells is inhibited more efficiently because MAb binds to the spike and blocks the DPP4-dependent entry pathway, (ii) viral entry into Fc receptor-expressing cells is first enhanced and then inhibited because MAb binds to the Fc receptor to enhance the ADE pathway until the Fc receptor molecules are saturated, and (iii) viral entry into cells expressing both DPP4 and Fc receptor is first inhibited, then enhanced, and finally inhibited again because of the cumulative effects of the previous two patterns. https://jvi.asm.org/content/jvi/early/2019/12/05/JVI.02015-19.full.pdf
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