Superantigens of HIV in SARS-CoV-2

A possible link of SAgs Gp120 as Neurotoxin Agent in Covid-19

My previous article was about the SAgs (Superantigens) in Covid-19 that caused SEB (Staphylococcal enterotoxin B). The infection came from either Staphylococcus aureus or group A Streptococcus (GAS), also called Streptococcus pyogenes. SAgs are microbial proteins produced by various microorganisms that elicit excessive and strong stimulation of T cells via an unconventional mechanism. They interact with antigen-presenting cells (APCs) and T cells to induce T cell proliferation and massive cytokine production, which leads to fever, rash, capillary leak, and subsequent hypotension, the major symptoms of toxic shock syndrome. These symptomps were seen in children with Multi-system Inflammatory Symptomps (MIS) inducted by SARS-CoV-2.

Known viral SAgs are mouse mammary tumor virus (MMTV), rabies virus, Epstein-Barr virus (EBV), human endogenous retrovirus (HERV), human immunodeficiency virus (HIV), and Ebola virus.

The proteins which are identified as SAgs of HIV are Nef and gp120. The massive activation of CD4+ T cells in early stages of infection and clonal deletion, energy and apoptosis of bystander T cells in the late stages may be due to SAg property of Nef protein, as well as the other mechanisms. HIV gp120 glycoprotein is a B-cell SAg that binds to VH3-expressing B cell receptors and causes polyclonal B cell activation. In addition, binding of gp120 to IgE on the surface of basophiles and mast cells causes activation of those cells, secretion of high level proinflammatory mediators leading to allergic reactions and tissue damage.

Prada et al reported that 4 insertions in the spike glycoprotein (S) which are unique to the 2019-nCoV and are not present in other coronaviruses. The amino acid residues in all the 4 inserts have identity or similarity to those in the HIV-1 gp120 or HIV-1 Gag, from Asia and Africa. The inserts are being discontinuous on the primary amino acid sequence. The 3D-modelling of the 2019-nCoV suggests that they converge to constitute the receptor binding site.

Envelope glycoprotein GP120 (or gp120) is a glycoprotein exposed on the surface of the HIV envelope. It was discovered by Professors Tun-Hou Lee and Myron “Max” Essex of the Harvard School of Public Health in 1988. The 120 in its name comes from its molecular weight of 120 kDa. Gp120 is essential for virus entry into cells as it plays a vital role in attachment to specific cell surface receptors. These receptors are DC-SIGN, Heparan Sulfate Proteoglycan and a specific interaction with the CD4 receptor, particularly on helper T-cells. Binding to CD4 induces the start of a cascade of conformational changes in gp120 and gp41 that lead to the fusion of the viral membrane with the host cell membrane. Gp 120 has been claimed previously to be homologous to parts of snake venom neurotoxins and rabies virus glycoprotein ("the neurotoxic loop"). Gp120 was directly toxic to brain endothelial cells and cause the blood-brain barrier (BBB) disruption. BBB compromise is associated with neurocognitive impairment, and the combination of elevated plasma viral load and BBB compromise may increase the risk for development of HIV-associated dementia (HAD).

SARS-CoV-2 binds to cells via the S1 subunit of its spike protein. Intravenously injected radioiodinated S1 (I-S1) readily crossed the blood–brain barrier in male mice, was taken up by brain regions and entered the parenchymal brain space. I-S1 was also taken up by the lung, spleen, kidney and liver. Intranasally administered I-S1 also entered the brain, although at levels roughly ten times lower than after intravenous administration.

The HIV-1 Gag protein enables interaction of virus with negatively charged host surface (Murakami, 2008) and a high positive charge on the Gag protein is a key feature for the host-virus interaction.

Sources:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165073/

https://pubmed.ncbi.nlm.nih.gov/27525406/

https://www.researchgate.net/publication/338957445_Uncanny_similarity_of_unique_inserts_in_the_2019-nCoV_spike_protein_to_HIV-1_gp120_and_Gag/link/5e34c905a6fdccd9657c052b/download

Murakami, T. (2008). Roles of the interactions between Env and Gag proteins in the HIV-1 replication Cycle. Microbiology and Immunology, 52(5), 287–295. https://doi.org/10.1111/j.1348-0421.2008.00008.x

https://en.m.wikipedia.org/wiki/Envelope_glycoprotein_GP120

https://pubmed.ncbi.nlm.nih.gov/8470367/

https://www.hindawi.com/journals/tswj/2012/482575/

http://directory.umm.ac.id/Data%20Elmu/jurnal/B/Brain%20Research/Vol879.Issue1-2.2000/16813.pdf

https://www.nature.com/articles/s41593-020-00771-8