A hypothetical biological pathway that may link SARS CoV 2 vaccinations to giant cell pathologies, via CD4 derangement due to receptor binding of HIV GP 120 homologous regions, Part 1
To link prior concepts together, and evaluate the potential risks if HIV GP 120 homology is present in vaccination end products, more contextual information is needed. My prior article concerning the NLS and HIV homologous regions, needs a bit more expounding. For one, What is HIV glycoprotein 120 used for in a natural HIV infection? Also, how much homology was actually found, are the studies legit and how meaningful are sections of that size generally?
HIV glycoprotein 120 is a membrane protein. It is part of a membrane protein complex, when assessed with its anchor GP41. Three glycoprotein 120 molecules are each linked to a GP41 molecule, which also anchor said complex to the viral membrane.
”The HIV viral membrane contains 14 ‘spikes’ (±7), gp160 complexes consisting of three gp120 proteins each linked to a gp41 protein in a tripod shape [1, 2]. These ‘spikes’, anchored into the viral membrane by gp41, allow the virus to attach itself onto host cells. The gp160 complex binds with the CD4 receptor on the host cell membrane, then the gp120 associates with a chemokine receptor and dissociates completely from the gp41 allowing the viral membrane to fuse with that of the host . Gp120 contains five variable regions, or loops  interspersed with five conserved regions (see Fig. (1). The glycoprotein is a globular structure that folds to form an ‘inner’ domain (containing the N and C termini, which in intact Env would associate with gp41), an ‘outer’ domain, and a ‘bridging sheet’ that links the inner and outer domains. The CD4 binding site is located in the ‘pocket’ between the inner and outer domain and above the bridging sheet. All three domains are important for CD4 and coreceptor binding. Glycosylation is found over much of the surface of the protein, and particularly on the outer domain and the ‘immunosilent face’ that contains the V4 and V5 variable loops”
Sound familiar? The structure appears to be very similar to how the spike protein functions in SARS CoV 2. They are both Class 1 fusion glycoprotein trimers that facilitate viral membrane fusion, after cleavage via cellular proteases.
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This particular viral construct can be used as a method of cell entry, but has also been shown to have deleterious effects on CD4 cell signaling in HIV infections
“Gp120 is essential for viral infection as it facilitates HIV entry into the host cell and this is its best-known and most researched role in HIV infection. However, it is becoming increasingly evident that gp120 might also be facilitating viral persistence and continuing HIV infection by influencing the T cell immune response to the virus. Several mechanisms might be involved in this process of which gp120 binding to the CD4 receptor of T cells is the best known and most important interaction as it facilitates viral entry into the CD4+ cells and their depletion, a hallmark of the HIV infection. Gp120 is shed from the viral membrane and accumulates in lymphoid tissues in significant amounts. Here, it can induce apoptosis and severely alter the immune response to the virus by dampening the antiviral CTL response thus impeding the clearance of HIV”
and, from another paper
“Binding of gp120 to CD4 on the cell surface may also lead to CD4+ cell depletion by inappropriate immune targeting, and may interfere with CD4+ cell function and ontogeny by disrupting CD4-mediated cell signaling”
As already previously established, there are sequence alignments that claim “homology”to this HIV protein, for certain portions of the SARS CoV 2 spike glycoprotein. But how viable are they? Are the sections of amino acids actually long enough to mean anything? Where are they in the 3D spike structure? These are all valid critiques that most scientists will levy, and that some will cling to, in an attempt to debunk what I am about to cover.
First: their length. One of these inserts contains the furin cleavage site (insert 4, which does NOT come together with the other 3 in the 3D model. It is nestled underneath them, and is visible in an image below, lime green outside the red circle on the spike protein 3D image. I am merely using it here, to give an example of the potential importance of short sequences). This furin cleavage site is only 5 amnio acids long (PRRAR) and is a vital point in the protein for cleavage and function. Altering just a single amino acid here, is likely what has caused the omicron variant to have reduced furin cleavage affinity. The amount of amino acids that may actually be used to bind to a receptor, can also be rather low, as this supplemental assessmentof a GP 120 binding loop also shows
This is an assessment of a HIV variant I am unfamiliar with, but it’s important to now note that these loops are called variable loops, and they contain the amino acids responsible for immune cell receptor binding in normal HIV infections. They are capable of rearranging their order and critical amino acids to facilitate and enhance immune evasion, enabling them to evade cells that may be wise to some versions of them. This shows us that in HIV GP 120, the exact order of these acids is not overly important. On the contrary, they are actually protected by their sequence diversity, as well as glycosylation, most importantly N linked glycosylation.
So, now knowing what amino acids can be used by a GP120 variable loop, and that N linked glycosylation plays a role in immune evasion as well as perhaps receptor affinity for DC signwe can now perhaps postulate on the order of some of our amino acids found in our "inserts". Do any of these inserts have similar amino acids as seen above, or have N linked glycosylation?
if so, where do they sit in the 3d model? can they even touch a receptor, or are they for structure in SARS CoV 2?
I can say, yes, those amino acids do appear in our inserts
Particularly, insert 3, and N linked glycosylation does occur, particularly in inserts 1 and 2
N linked glycosylation corresponding to the sequences above, below. The second N in the NN doublet of insert 2, and the first and only N of insert 1, are where N linked glycosylation in inserts 1 and 2 are found
Matching binding amino acids in the “CD4 binding loop” are S, G, and D. Other acids that also match but weren’t labeled as “gp120 contacts”, are T and P
But what about where they land in the quaternary structure
So far, we have answered a couple of our questions:
What is HIV glycoprotein 120 used for in a natural HIV infection?
(A. immune cell receptor binding)
How meaningful are sections of that size generally?
(A. The furin cleavage site is 5 amino acids in SARS CoV 2 and the entire CD4 binding loop is 10 amino acids long in a on record CD4 binding loop in GP 120. It is safe to assume, that short sequences in amino acid chains can be thus incredibly functionally important in receptor binding or membrane fusion)
We have also begun to provide abundant evidence, that these particular amino acids may play a role in causing the SARS CoV 2 spike to bind to immune cell receptors, via the exact claimed HIV GP120 homology regions that were found by the pulled Pradhan preprint. The presence of both N linked glycosylation, and on record CD4 binding amino acids, plus all those regions coming together in close proximity in the 3D model, is adequate cause for suspicion and worry.
We still need answers for:
how much homology was actually found?
are the studies legit?
I can not answer one of these. As is, I do not have any experience using BLAST, and I can not reproduce the Pradhan alignment. However I have already confirmed that their amino acid sequence is at least completely correct, and it does indeed match the Wuhan Hu 1 spike.
As for the other one, “how much homology was found”, we can simply count the amino acids in inserts 1, 2, and 3, since they all come together next to each other in the N and C terminal domains.
(A. 6 homologous acids in insert 1, 6 acids in 2, and 12 in 3, so excluding insert 4, that’s 24 amino acids homologous to GP120)
It is important to keep in mind that these regions in the pradhan alignment are homologous to variants of HIV, and not the HIV reference sequence. Also remember that these regions are under suspicion are indeed highly variable
Further articles will explore more evidence and will begin to find real world examples of clinical possibilities that may arise, if these GP 120 inserts are indeed capable of binding to or interfering with immune cell receptors, such as CD4 receptors or DC sign
This article is also a rough draft and a work in progress. As such it may change in the future. If mistakes are found, bolded amendments will be applied later, to make clear what has been altered.
The GP120 Molecule of HIV-1 and its Interaction with T Cells
Current Medicinal Chemistry
Volume 17, Issue 8, 2010
Page: [741 - 749]
A video of the scientist who applied the 2P mutation into the vaccine spike, covering how the spike functions normally
3:30 - 5:09
Class I and class II viral fusion protein structures reveal similar principles in membrane fusion (Review)
David J. Schibli and Winfried Weissenhorn*European Molecular Biology Laboratory (EMBL), 6 rue JulesHorowitz, 38042, Grenoble, France
The CD4-gp120 interaction and AIDS pathogenesis
Annual Review of Immunology
Vol. 9:649-678 (Volume publication date April 1991)
Structural Basis for Broad and Potent Neutralization of HIV-1 by Antibody VRC01
(Supp Fig 1.)
Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9
HIV-1 Envelope Glycoprotein Variable Loops Are Indispensable for Envelope Structural Integrity and Virus Entry
AIDS Institute, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
Human Immunodeficiency Virus Envelope (gp120) Binding to DC-SIGN and Primary Dendritic Cells Is Carbohydrate Dependent but Does Not Involve 2G12 or Cyanovirin Binding Sites: Implications for Structural Analyses of gp120-DC-SIGN Binding
JOURNAL OF VIROLOGY, Dec. 2002, p. 12855–12865 Vol. 76, No. 24 0022-538X/02/$04.000 DOI: 10.1128/JVI.76.24.12855–12865.2002 Copyright © 2002, American Society for Microbiology.
Cell Host & Microbe
Volume 28, Issue 4, 7 October 2020, Pages 586-601.e6
Virus-Receptor Interactions of Glycosylated SARS-CoV-2 Spike and Human ACE2 Receptor
Handbook of Cell Signaling (Second Edition)
2010, Pages 97-101
Chapter 15 - HIV-1–Receptor Interactions