key: cord-0915775-wmelyonk
authors: Roe, Kevin
title: A proposed treatment for pathogenic enveloped viruses having high rates of mutation or replication
date: 2020-07-08
journal: Scand J Immunol
DOI: 10.1111/sji.12928
sha: 33b210ef8b7a21e38205231055783f0dad19cb92
doc_id: 915775
cord_uid: wmelyonk

Several enveloped viruses, particularly some RNA viruses, have high rates of mutation or replication, which can make them virulent pathogens in humans and other mammals. A proposed treatment could use synthesized proteins to mask pathogenic viral surface proteins to quickly induce an immune attack on specific enveloped viruses by using existing immune cells. One treatment could inject dual‐protein ligand masks into patients' blood streams to mask pathogenic surface proteins used to infect mammalian cells. The mammalian immune system already uses an analogous, more complex structure called a pentraxin to neutralize some pathogens by connecting their surface proteins to immune cells. And several types of antiviral peptides have already experimentally demonstrated effectiveness in blocking various viral pathogen infections. These treatments offer advantages, especially for currently untreatable viral pathogens. Furthermore, using dual‐protein ligands and the antigenic memory of some subpopulations of NK cells would also allow the creation of defacto vaccines based on a host's NK cells, instead of vaccines utilizing CD4 and CD8 α:β T cells, which are limited by the requirement of MHC presentation of the target antigens to α:β T cells. Targeted NK cell vaccines could attack host cells latently or actively infected by intracellular pathogens, even host cells having pathogen downregulated MHC antigen presentation. Eight postulates concerning the effects of pathogen mutation, or change in phenotype from genetic recombination or rearrangement, and replication rates on pathogen versus host dominance are also listed, which should be applicable to viral and non‐viral pathogens.

Every human has barrier surfaces to suppress viral infections through the epithelium of the respiratory system and the gastrointestinal tract, the endothelium of blood vessels, placental barrier tropoblasts, and skin. 1 The 2018b.v2 report of the International Committee on Taxonomy of Viruses (ICTV) lists 1019 viral genera and 5560 viral species. 2 But only a small percentage are pathogenic to humans, and presently 155 viral genera are known to cause human viral diseases. 3 Yet despite anti-viral medicines and vaccines, pathogenic viruses infect millions of children and adults yearly world-wide. [1] [2] [3] [4] Even though some viral infections can be treated or at least avoided by vaccination, for many of the untreatable viral infections, a large fraction of the survivors frequently suffer mild to severe life-long impairments. For example, the Eastern Equine Encephalitis (EEE) virus, endemic to the Western Hemisphere, has no human vaccine or even a treatment, and has been called the most deadly mosquito-borne pathogen in North America, because it can kill 35% to 75% of infected humans depending on the medical care received, and an estimated 35% to 50% of the survivors suffer severe and permanent neurological brain damage. [5] [6] This makes the need for a EEE virus vaccine obvious, but the only vaccine currently available is for horses, not humans. 6 Another untreatable and lethal virus, transmissible by bodily secretions of humans and other mammals, and even considered fully capable of a world-wide pandemic spread after mutation, is the Nipah virus, with a mortality rate ranging from 72% to 86% in the Indian subcontinent. 7-10 Peptide inhibitors against the Nipah virus have been designed and modeled to target and inhibit interacting sites on the viral attachment G receptor, the F fusion protein trimer used to fuse the viral envelope with the host cell membrane, and the M matrix protein dimer used for initiating the budding of the virus; and the bonding stabilities of various antiviral peptide inhibitors were assessed with molecular dynamics (MD) simulations. 11 But at this time, there is still no vaccine and not even a treatment for humans.

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The two preceding viruses illustrate the virulence of some viral pathogens after transmittal to humans, but some extremely virulent viruses can have both high rates of mutation and high rates of replication. Some DNA viruses, and particularly several RNA viruses, have high mutation rates, which can be expressed as nucleotide substitutions per nucleotide per cell infection (s/n/c); and these mutation rates typically range from 10 -8 to 10 -6 s/n/c for DNA viruses to 10 -6 to 10 -4 s/n/c for RNA viruses, although nucleotide insertions and deletions can also make a smaller contribution to the overall mutation rate. 12 And independently from mutation rates, some viral pathogens can have a high replication rate among host cells, especially after transmission to secondary hosts of other species, such as viruses that originally evolved high replication rates while they infected animals such as bats and were thus selected by the fast immune responses of bats. 13 [13] [14] And it will obviously be quite challenging to treat virulent viruses that have both high mutation rates and high replication rates.

However, there are several known antiviral peptides that can inhibit or block viral infections, and some of them could potentially treat infections by virulent enveloped RNA viruses having high rates of mutation and replication. [15] [16] There are even databases of experimentally verified antiviral peptides, typically derived from micro-organisms. 16 These antiviral peptides are members of the larger group of antimicrobial peptides that contribute to the innate immune response of many species, and they are known to act either directly or by creating an immune response. 17 Several antiviral peptides have been experimentally demonstrated to be effective against different viruses, even in serum solutions with micro-molar concentrations, and their actions typically include blocking one or more stages of a virus's infection cycle; such as host cell attachment, host cell entry, replication inside a host cell, transcription, translation, maturation, or release from a host cell. [18] [19] This paper is focused on antiviral applications of custom designed dual-protein ligand masks that can be synthesized by conventional recombinant DNA biotechnology, and these ligand masks are Accepted Article theoretical and functional analog extensions of pentraxins, which are more complex immune structures used by the mammalian immune system to neutralize some pathogens. 20

In targeting specific viral pathogens, dual-protein ligand masks (for brevity, henceforth called dualprotein ligands) should be able to create a quick and powerful immune memory response with existing memory immune cells against some viral pathogens or virus infected cells, without some of the practical limitations of vaccines.

Which viral pathogens or virus infected cells are susceptible to memory T cell and memory B cells?

Enveloped viruses, and some non-enveloped viruses, typically have pathogenic surface proteins, such as glycoproteins, needed for viral infection of host cells. [8] [9] Some of these surface proteins cannot mutate too much without losing their functionality for infection of a host cell, so critical sections of these essential surface proteins can be targeted to block viral pathogen infections.

Most T cell activations require that an antigen (i.e., a molecular pattern that a patient's immune system recognizes as foreign to the patient) be presented by another cell, such as a dendritic cell, on a specific surface protein known as a major histocompatibility complex (MHC), in humans this is also called a human-leukocyte-associated (HLA) protein. 21 T cells predominantly are α:β T cells with the MHC requirement for antigen presentation to activate α:β T cells; whereas a different subset of T cells called γ:δ T cells have no need for any MHC presentation. 22 Although activating γ:δ T cells is challenging, there are several distinct sub-populations of γ:δ T cells; while they are more abundant in mucosal tissues, sub-populations of γ:δ T cells are also found in several types of tissues and they are even found in blood. 22-25 Furthermore, γ:δ T cells can be transformed into memory T cells like α:β T cells; and for γ:δ T cell sub-populations residing in various tissues, peptides of distinct proteins, such as an endothelial protein C receptor β sheet, in the presence of other co-stimulating peptides of proteins, such as ICAM-1 (known also as CD54) can activate their γ:δ T cell receptors. [23] [24] [25] Activating the γ:δ T cell receptor and

This article is protected by copyright. All rights reserved one or two co-stimulatory receptors, can activate γ:δ T cells, which can also result in antibody production by activated B cells. 26 So γ:δ T cells are the T cells referenced herein.

Dual-protein ligands could make specific viral pathogens targets for existing immune memory cells or innate immune cells. Dual-protein ligands could induce an immune response by mimicking the key parts of antigens that activate existing immune memory cells or innate immune cells to attack tagged viral pathogens.

There are significant benefits in using the immune memory system to neutralize viral pathogens. One benefit is that when memory immune cells are triggered by a dual-protein ligand antigen, the antibody response of the immune memory system will produce antibody numbers much larger than the antibody numbers released by a primary immune response, or released by long lived plasma cells resident in the bone marrow, or B cells in the respiratory and intestinal mucosal tissue. 27 Other potential benefits of using dual-protein ligands include avoiding the need to use many different preventative anti-viral vaccinations, and sufficient mass bondings to pathogenic viral surface proteins could potentially minimize T cell death (lymphopenia) from too many inflammatory stimulating signaling proteins (a "cytokine storm") caused by some viral pathogens, such as the Ebola virus. 28

In summary, surface proteins are used by viral pathogens to infect mammalian cells. However, dualprotein ligands could mask and block these surface proteins before the widespread viral pathogen infection of mammalian cells.

A suggested treatment for humans uses a dual-protein ligand, that includes a first protein ligand that will mask (i.e., specifically bond to) a unique virus surface protein, or alternatively bond to a distinctive surface protein of a virus infected cell, and a second protein ligand that matches or mimics the section of an antigen that would activate memory immune cells, wherein the second protein ligand is connected to the first protein ligand. Both the first protein and the second

This article is protected by copyright. All rights reserved protein ligands can separately have their three dimensional conformations strengthened by covalent disulfide bonds (S-S bonds) formed between the sulfhydryl (-SH) groups of precisely placed cysteine amino acid residues. 29 Both the bonding between the first protein ligand to a viral surface protein, and the bonding between the second protein ligand to an immune cell, could be bondings utilizing non-covalent forces, such as electrostatic forces, van der Waals forces, hydrophobic forces, cation-pi interactions and hydrogen bonds. 30 Some component amino acid residues can produce several bonding forces; the aromatic amino acid residue tyrosine is typical and can bond by hydrogen bonding, hydrophobic forces, and through it's side chain pi-electron system have cation-pi interactions with nearby cations. 30 In the brain or central nervous system (CNS) especially, synthesis of the second protein ligand to mimic an antigen to cause an attack on virus infected cells by memory γ:δ T cells must also take into consideration the risk of excessive inflammation. There are several sub-populations of γ:δ T cells, that can be distinguished by their T cell receptor variable regions (Vγ), and they can be separated into bigger classifications, such as γ:δ T1 cells and γ:δ T17 cells. 26 However, there are some classifications of γ:δ T cells, the pro-inflammatory interleukin-17 producing γ:δ T17 cells for example, that can stop certain infections, but they can also potentially create excessive inflammation and promote cancers and some auto-immune diseases. 31 Other alternatives for treatments involving the CNS and brain are second protein ligands that utilize the less inflammatory γ:δ T1 cells, which are relatively scarce in blood, but more common in tissues and organs, that produce interferon-γ, which activates macrophages, but this can also cause some inflammatory interleukin-6 release. 32 Some potential ligands that could be mimicked by the second protein ligand to activate the γ:δ T cell receptors are listed later in this paper in the section that discusses the NK cell activating receptor NKG2D.

Another alternative is to synthesize a second protein that utilizes specific innate immune cells. One option is the microglia, the main resident macrophages for neurons in the CNS and brain, and they and CNS border-associated macrophages in general are among the innate immune cells that could be used. 33 Microglia are essentially Accepted Article macrophages, so the second protein ligand could be synthesized to bond to one of the many distinct types of receptors expressed by macrophages -including the pattern recognition receptors (PRR), such as the Toll-like receptors, the Fc antibody receptors, or the complement receptors such as CR3, for example. 34 The receptor structures of some macrophages and other immune cells, such as the NK cell NKG2D activating receptor, are known to some extent; but any targeted receptor structure will probably require considerable research to determine enough detailed structure to enable the design of a second protein ligand having a strong bond to the targeted immune cell receptor. The NK cell NKG2D activating receptor and the structure of its ligands are discussed in more detail later in this paper.

There are several potential surface proteins on specific viral pathogens that can be targeted. For example, these surface proteins include the glycoproteins E1 and E2 on the surface of the hepatitis C virus of the Hepacivirus genus. 35-36 Another example is human immunodeficiency virus 1 (HIV-1), an enveloped virus of the Lentivirus genus with a surface protein, a trimeric glycoprotein, to induce membrane fusion for viral entry into a human host cell, and this glycoprotein is known to be targeted by antibodies. 37 Measles virus is an enveloped virus of the Morbillivirus genus, with a morbillivirus surface protein complex with tetrameric attachment (H) and trimeric fusion (F) glycoproteins for viral entry and infection of human host cells. 38 Eastern equine encephalitis virus is an enveloped virus of the Alphavirusgenus with two trans-membrane envelope glycoproteins E1 and E2, where the surface protein E2 bonds to human cells for viral entry. [39] [40] In summary, there are several possible target viral surface proteins for bonding to dual-protein ligands for the immune system neutralization of viral pathogens. As previously discussed, the structures of some viral surface proteins are already known to some extent; but any targeted viral surface protein will probably require considerable research to determine enough detailed structure to enable the design of a first protein ligand having a strong bond to the targeted viral surface protein.

This article is protected by copyright. All rights reserved One treatment option injects dual-protein ligands into the blood stream or localized regions to mask pathogenic surface proteins used by viruses to infect mammalian cells. The dosage of dual-protein ligands necessary to treat a viral pathogen infection will vary, depending on how long the dual-protein ligands will reside inside the patient before they are removed or inactivated, depending on the concentrations of the targeted virus and the immune cell utilized, and depending on how strongly each dual-protein ligand will bond with both the targeted viral surface protein and the immune cell utilized.

The strength of bonding between ligands and proteins is quantified by an association constant (K a ), which is defined as the equilibrium molar concentration of a protein bound to a ligand, divided by the multiplication of the molar concentration of the unbound ligand and the molar concentration of the unbound protein, as seen in equation (1). 41 Other papers use the dissociation constant (K d ), the reciprocal of the association constant K a , as seen in equation (2) As mentioned before, a different option is utilizing cells of the innate immune system (e.g., innate lymphoid cells, macrophages or other phagocytes). As a specific example, the first protein ligand would bond to either a surface protein of a viral pathogen, or bond to a surface protein of a cell infected by the viral pathogen, and the second protein ligand would be designed to strongly bond to and activate phagocytes to consume the viral pathogen or the virus infected cell, by designing the second protein ligand to bond to a surface protein of human macrophages or neutrophils, for instance the FcαRI receptor (CD89). 42 This option would bypass some viral defenses against memory T cells or B cells, and would also quickly initiate an attack by innate immune system cells, in this instance by phagocytic cells.

An injection of dual-protein ligands into the blood stream of patients will be easier than trying to introduce dual-protein ligands from inside the gastrointestinal tract, whether by using oral capsules or therapeutic bacteria. [43] [44] And injections into the blood stream, or injections into Accepted Article localized regions, can be used separately or in a combination. A combination of both treatment approaches is probably better for treating viral pathogen infections that also include the brain or CNS.

In such cases, a lumbar puncture through the patient's spine can safely inject the dual-protein ligands into the cerebrospinal fluid of the patient, and this is a standard procedure to deliver antibiotics directly into the brain and CNS, while avoiding the blood brain barrier, a serious impediment to introducing most medicines into the brain by blood circulation. 45 These proposed treatments raise the question of whether there is any risk of creating dangerous immune system reactions by injections of dual-protein ligands. This risk is small, because as discussed in an earlier paper, by themselves most pure proteins and peptides rarely induce an immune response. 46 This is one motivation to combine a chemical adjuvant with many vaccinations to make their antigens immunogenic to induce a strong immune response, and influence the antibody titer and isotype and increase cell-mediated responses. 47 However, since memory T cells and memory B cells already are activated effector cells, dual-protein ligand injections should be able to activate these targeted memory cells without requiring any adjuvants combined with the injections. But including certain cytokines can be helpful; cytokine therapies using Type I interferons and interleukin-2 have been approved for some cancer treatments; and specific cytokines help NK cell receptor activation, which will be discussed in more detail later. 48

It should be possible to synthesize dual-protein ligands in advance in the quantities needed to stop viral pathogens at relatively low cost. The modification of bacterial genomes, such as the genome of Escherichia coli, using restriction enzymes can induce expression of specific and desirable peptides and proteins, and this is a very mature and long commercialized technology. 49 Thus, recombinant DNA techniques, applied to one of the commercially available strains of bacteria, could make dualprotein ligands. protein ligands having an equivalent number of amino acid residues, this implies that entire dualprotein ligands could be synthesized with several hundred amino acid residues, in some cases with as little as 600 amino acid residues, possibly including a short section between the first protein ligand to the second protein ligand to provide more flexibility. Each protein ligand only needs to be long enough to provide a strong bond with its respective target, and each protein ligand may need conformal stabilization provided by disulfide bonds between precisely placed cysteine amino acid residues within each protein ligand.

One last question concerns the therapeutic duration of the dual-protein ligands in the blood stream of a mammal. One significant factor determining the duration of a dual-protein ligand will be the presence and concentrations of pathogen and mammalian proteolytic enzymes, also known as proteases or peptidases, having nucleophilic active sites, that typically cleave peptide bonds by hydrolysis, such as at the carbonyl (C=O) of the peptide bond. 59 Any peptide segment of the dualprotein ligand is a potential peptidase target, but the peptide segment in the linkage of the two protein ligands of a dual-protein ligand will be particularly accessible to peptidases. Fortunately, many peptidases also have known inhibitors, and carefully chosen specific inhibitors for the most inconvenient peptidases could also be injected with the dual-protein ligands to prevent or slow peptidase attacks, preferably without causing major disruption to the normal physiological functions of mammalian peptidases. The most appropriate inhibitor for a peptidase can be found in an extensive database of peptidases, their substrates and their

This article is protected by copyright. All rights reserved inhibitors, such as the MEROPS database. 60 As of September 2017, there were 5267 peptidase identifiers and 868 inhibitor identifiers listed in the MEROPS 12.0 database, along with the peptidase's substrate. 60

Eight postulates concerning the effects of pathogen mutation, pathogen change in phenotype by genetic recombination and pathogen replication rates on pathogen versus host dominance are listed below and should be applicable not only to viral pathogens, but also applicable to bacterial, fungal, and protozoan pathogens. The term "pathogen strain" as used below is defined as a sub-species or sub-type of a pathogen species. The term "dominate" as used below is defined as survive, or at least maintain an infection, where a pathogen strain possibly, but not necessarily, could kill its host;

whereas when a host "dominates" a pathogen strain, it may, or may not, be able to eliminate the pathogen strain. The term "mutation" as used below is defined as random changes in one or more genetic nucleotides, by substitution, deletion or insertion of nucleotides, etc. The term "beneficial mutation" as used below is defined as a mutation that helps the pathogen strain, against the host or against other pathogen strains. A "beneficial change in phenotype" as used below is also defined as helping the pathogen. The term "genotype" as used below is defined as the entire genome of a pathogen strain, and the term "phenotype" as used below is defined as the characteristics of a pathogen strain, expressed as the interaction of a pathogen strain's genotype with its age, its various conditions of activity or latency, or its environment. It should be noted that a pathogen's phenotype can also change as a result of genetic recombination or rearrangement (called "genetic recombination" for brevity henceforth), either randomly or by programming, recombining or rearranging groups of nucleotides within a single pathogen strain or from multiple pathogen strains; such as a change in viral phenotype after random genetic recombination during co-infection of a host cell by two different viral strains. 61 One specific example of a viral change in phenotype would be the antigenic shift in one or more antigenic determinants of an influenza virus resulting from the genetic recombination of various bird and mammalian influenza virus strains. 61

A beneficial mutation for a pathogen strain could be a higher rate of replication, an improvement in its infectivity or the transmission of the pathogen strain, an improvement in reducing environmental, resource or metabolic requirements for the survival, replication or spread of the pathogen strain, an improvement in evading or overcoming the immune defense of a host by changing one or more antigenic determinants, and so forth. And as previously discussed, a beneficial change in phenotype by genetic recombination of a pathogen strain can possibly result in an antigenic shift in one or more antigenic determinants that were essential to the host's immune system for recognition and defense against the pathogen strain.

Examples of how the effectiveness of host defenses could be improved include an improved blocking of the infectivity of the pathogen, or an improvement in targeting, accessing or in neutralizing the pathogen, such as provided by adaptive immune system immunoglobulin antibody isotype switching or somatic hypermutation and affinity selection of antibodies against the pathogen, producing more effective cytokines, activating other more effective innate or adaptive immune cells, and so forth. 27, 62 Introduction of medicines or treatments are an alternative equivalent means to improve the effectiveness of the host defenses.

A host can replicate effective defenses include increasing the number of effective antibodies, increasing the number of innate or adaptive immune cells, increasing the number of effective

This article is protected by copyright. All rights reserved cytokines, increasing the number of activated immune cells, and so forth. Introduction of medicines or treatments are an alternative equivalent means to replicate host defenses faster.

recombination against a first host's immune defenses faster than its first host can improve the effectiveness of its immune defenses will dominate its first host, and after transmission to a second host it will be enabled to more virulently dominate a second host individual or species having a slower or weaker immune defense, which otherwise provides an equivalent host environment for the pathogen strain.

host environment for the pathogen strain.

can beneficially mutate or beneficially change its phenotype by genetic recombination against the host's immune defenses can eventually dominate the pathogen.

replicate can eventually dominate the pathogen.

This article is protected by copyright. All rights reserved These eight postulates summarize the effects of pathogen mutation, pathogen change in phenotype by genetic recombination, and pathogen replication rates on pathogen versus host dominance and their scope is limited to pathogen versus host dominance, but these postulates should be applicable to viral pathogens, and also applicable to bacterial, fungal, and protozoan pathogens. The host could be a mammal, but could possibly be non-mammalian, or even outside of the animal kingdom, since plants also struggle for dominance over several types of pathogens.

Targeted dual-protein ligands could mask viral surface proteins to quickly treat some untreatable virus infections by using already existing immune cells. One treatment uses injection of the dual-protein ligands into the blood of patients, and another treatment injects the dual-protein ligands into less accessible viral pathogen infections, such as the brain or central nervous system, to bond to a viral surface protein used to infect mammalian cells. These treatments could have advantages, especially for enveloped RNA viruses having high rates of mutation or replication, although the initial development and implementation of these new treatment approaches will require substantial resources. Furthermore, using dual-protein ligands and the antigenic memory of some subpopulations of NK cells would also allow the creation of defacto vaccines based on a host's NK cells, instead of vaccines based on α:β T cells, which are limited by the requirement of MHC presentation of the target antigens to α:β T cells. Targeted NK cell vaccines could attack host cells latently or actively infected by intracellular pathogens, even host cells having less MHC antigen presentation capabilities, such as neurons. Eight postulates concerning the effects of pathogen mutation, or change in phenotype from genetic recombination or rearrangement, and replication rates on pathogen versus host dominance have also been listed, which should be applicable to viral and non-viral pathogens.

The author confirms that the ethical policies of the journal, as noted on the journal's author guidelines page, have been adhered to. No ethical approval was required as this is an article with no original research data.

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

The author attests that he conceived the paper, wrote the paper, and approved the final version of the manuscript, and attests that he meets all of the ICMJE criteria for authorship. 

Type III interferons in antiviral defenses at barrier surfaces

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Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young childer in 2015: a systematic review and modelling study

Eastern equine encephalitis virus -old enemy

Heparan sulfate binding by natural eastern equine encephalitis viruses promotes neuro-virulence

Morbidity and mortality due to Nipah or Nipah-like virus encephalitis in WHO South-East Asia Region

World Health Organization Nipah virus infection. World Health Organization

Zoonotic potential of emerging Paramyxoviruses: knowns and unknowns

Accepted Article This article is protected by copyright. All rights reserved 11

Viral mutation rates

Accelerated viral dynamics in bat cell lines, with implications for zoonotic emergence

Appendix -Structure, genome organization, and infectious cycles

Viral escape from endosomes and host detection at a glance

AVPdb: a database of experimentally validated antiviral peptides targeting medically important viruses

The gamma interferon(IFN-gamma) mimetic peptide IFNgamma (95-133) prevents encephalomyocarditis virus infection both in tissue culture and in mice

HIPdb: a database of experimentally validated HIV inhibiting peptides

AVPpred: collection and prediction of highly effective antiviral peptides

Pentraxins in the activation and regulation of innate immunity

Protective immunity against Hepatitis C: many shades of gray

Human Vδ2 versus non-Vδ2 γδ T cells in antitumor immunity

Tissue adaptations of memory and tissue-resident gamma delta T cells

Cytomegalovirus and tumor stress surveillance by binding of a human γδ T cell antigen receptor to endothelial protein C receptor

Endothelial cell protein C receptor-dependent signaling

Six-of-the-best: unique contributions of γδ T cells to immunology

IgE repertoire and immunological memory: compartmental regulation and antibody function

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Antigen recognition by B-cell and T-cell receptors

T cell receptor signaling for γδ T cell development

Gamma-delta γδ T cells: friend or foe in cancer development

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Identification of novel functions for hepatitis C virus envelope glycoprotein E1 in virus entry and assembly

Conformational states of a soluble, uncleaved HIV-1 envelope trimer

Measles virus fusion protein: structure, function, and inhibition

Cryo-EM structures of eastern equine encephalitis virus reveal mechanisms of virus disassembly and antibody neutralization

Protective antibodies against eastern equine encephalitis virus bind to epitopes 2 in domains A and B of the E2 glycoprotein

Antigen-antibody interactions: principles and applications

The humoral immune response

Stopping untreatable pathogen infections using peptide ligands to sabotage pathogenic cell surface proteins

Dual-peptide ligand masks: a proposed treatment approach to stop prion disease dementias

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Accepted Article This article is protected by copyright. All rights reserved 46. Roe, K. A proposed treatment approach to treat lethal mutating cancers

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Cytokines in the treatment of cancer

Construction of biologically functional bacterial plasmids in vitro

Toxoplasma gondii infection drives conversion of NK cells into ILC1-like cells

The "less-is-more" in therapeutic antibodies: afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity

Redefining memory: building the case for adaptive NK cells

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Two human ULBP/RAET1 molecules with transmembrane regions are ligands for NKG2D

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Influenza virus evolution, host adaptation and pandemic formation

Innate immunity

This article is protected by copyright. All rights reserved