Viral Molecules as Immunomodulators of T Lymphocyte Effect

Kee Whun Leo Dan Avila
Universidad Autónoma de Baja California, Baja California, Mexico
Correspondence to: keedna@gmail.com

DOI: https://doi.org/10.70389/PJI.100002

Additional information

• Ethical approval: N/a
• Consent: N/a
• Funding: No industry funding
• Conflicts of interest: N/a
• Author contribution: Kee Whun Leo Dan Avila – Conceptualization, Writing – original draft, review and editing
• Guarantor: Kee Whun Leo Dan Avila
• Provenance and peer-review:
  Commissioned and externally peer-reviewed
• Data availability statement: N/a

Keywords: viral immunomodulators, t lymphocyte differentiation, immune evasion, virokines, hepatitis c virus.

Peer Review
Received: 19 August 2024
Revised: 24 September 2024
Accepted: 30 September 2024
Published: 14 October 2024

Introduction

A variety of strategies exist to try to combat pathogenic microorganisms. While the search for novel, more efficient methods continues, these uninvited guests adapt and “outthink” the immune system and immunologists alike. Here, we describe immune evasion strategies employed by viral pathogens and how these adaptations could modulate the immune response in pathological immunity scenarios. Host-directed therapy, for example, is an emerging approach that interferes with host cell factors that a pathogen requires for replication or persistence. Host-directed therapy stimulates a protective immune response against a determined pathogen, reduces exacerbated inflammation, and balances immune reactivity at sites of pathology.¹

The Strategy

The strategy explored here intends to resurrect the use of viral molecules that drive the evasion of the host immune response as therapeutic pharmaceuticals, an idea first proposed with the discovery of virokines.² Virokines are viral proteins of high homology with immune system proteins. Virokines are regularly smaller and more effective than their counterparts, expressing various general and specific effects on the immune response. This review describes viral molecules with immunomodulatory potential related directly to T lymphocyte effector functions. Viral molecules harbor a variety of advantages when it comes to searching for or developing molecules as potential pharmaceuticals with specific activity and molecular targets. Recent bioinformatics tools have accelerated the search and organization of viral molecules with potent and exquisite selectivity. Even so, heightened interest and more research are still needed in the virokine field.^3–6

Pathogen Host Co-Evolutionary Relationship

The phenomenon of evolution requires selective pressure to occur. A pathogen-host interaction imposes selective pressure on both parties, giving way to adaptation and co-evolution. Specifically, pathogenic organisms require specific parameters to proliferate successfully at the host’s expense. Likewise, the host’s immune system responds to specific pathogenic intrusion. This interaction generates a double-sided selection where pathogen and host factors and their variations determine the outcome of this relationship. Various pathogens are known for evading or changing the host’s response, mainly that of the immune system.⁷ So, to counteract evasion and modification of pathogen-associated molecular patterns (PAMPs), the immune system generates variants, especially in the adaptive response, better suited to counteract the “new” intruders. This intense competition has driven back and forth the evolutionary characteristics of many, if not all, of the organisms seen today. Viruses have interacted with human hosts since our appearance on Earth.^8,9

Establishment of Viral Infections in Humans

Viruses are obligate intracellular parasites known to infect nearly all life forms on Earth. The outcome of these viral infections can be of two types: acute or chronic, both being either symptomatic or asymptomatic and ultimately leading to pathogenesis. An acute infection is of shorter duration than a chronic infection and tends to end with viral clearance by the host immune response. On the contrary, a chronic infection is an unresolved acute infection that recurs over a considerable portion of the host’s lifespan.¹⁰ For viruses to succeed in a complete infectious cycle, the interplay between host innate and adaptive immunity with virus-derived immune escape mechanisms should favor the latter.

T Lymphocyte Antiviral Immunity

Adaptive antiviral immunity divides into T lymphocyte and B lymphocyte activity. While B lymphocytes confer soluble circulatory protection, T lymphocytes engage in cell-to-cell interaction, cytokine expression, and cell destruction. The wide variety of T-cell subtypes in both CD8+ (cytotoxic T lymphocyte, CTL) and CD4+ (T helper, Th) T cells allows for variation and adaptability of the immune response.¹¹

CTLs

CTL antiviral activity is dogmatically related to the recognition and programmed destruction of pathogen-infected cells, all through the presentation of antigenic peptides. However, recognition through major histocompatibility complex class I (MHC I) peptide presentation is only the beginning of a humoral and cellular adaptive immune response. CTLs are prime cytokine and chemokine producers, allowing for the migration of other immune cells into sites of viral infections. In other words, an immune ambiance of soluble factors and cellular interactors comprises the core of the antiviral response, potentially orchestrated by peripheral MHC I sentinels, the CTLs.^12,13

Th Lymphocytes

Th lymphocytes play a role in the majority of adaptive immune challenges. A subtype of Th cells, known as Th1, defined by their expression of a specific transcription factor (TF) and cytokine, T-bet, and interferón-gamma (IFN-γ), indicates an immune response to viral infections. T-bet inhibits GATA-3 expression in these cells, limiting differentiation into a different effector cell, Th2, while promoting IFN-γ expression. IFN-γ inhibits viral replication, primes CTLs, and induces leukocyte migration.^14,15 T regulatory (Tregs) cells, an increasingly popular and controversial population of Ths, divide into thymus-derived natural Tregs (nTregs) and peripherally generated induced Tregs (iTregs). Characterized by CD4, CD25, and Foxp3 TF expression, Treg effector function is defined as the control and regulation of the immune response or immunosuppression.^16,17 Research on the role of Tregs during viral infections is controversial. On the one hand, Treg’s function during an acute viral infection benefits the host through immune homeostasis. On the other hand, a chronic viral infection has Tregs limiting the immune response due to viral proteins. In this event, the immune system suppresses T-cell activity, limiting immunopathology and favoring overall viral persistence.¹⁸

Cytotoxic CD4 T cells (CD4 CTLs) in antiviral immunity originated as an artifact. Experimental research in mice, macaques, and humans suggests that CD4 CTLs eliminate infected or transformed cells through the MHC class II (MHC II) surface proteins. MHC II antigen-presenting cells (APCs) include professional APCs, such as dendritic cells, macrophages, B cells, and various infected cell types. A couple of studies point out that the differentiation and appearance of CD4 CTLs occur when CTL activity is abrogated or eliminated.^19,20

General Mechanisms of Viral Immune Evasion

In biology, the continuity of viral pathogenesis points toward viral success in entry, replication, latency, and shedding. How viruses elaborate to achieve a complete life cycle utilizing such a limited number of proteins against the complexity of multicellular organisms is astounding. Gradually, research elucidates viral proteins’ immunomodulatory functions. Generated knowledge helps combat pathogenesis and provides potential molecular tools for treating or ameliorating other diseases. Diversity in immune evasion mechanisms translates into a higher success rate for completing a viral life cycle. Thus, viruses subvert antigen presentation, leukocyte migration, and other immunomodulatory checkpoints. Chan and Gack²¹ reviewed how viruses avoid or sabotage intracellular DNA and RNA sensing, limiting the induced expression of IFN-stimulated genes (ISGs). The resulting proteins of ISG stimulation target essential viral life cycle proteins and regulate immune sensing and establishment of the cytokine’s antiviral state. Different proteins in both cytoplasm and nucleus function to detect exogenous nucleic acid, consequently initiating the said antiviral state. Viral nucleotide sensing comes in various forms: Intracellular pattern recognition receptors (PRRs) such as Nod-like receptors, RIG-I-like receptors (RLRs), cyclic GMP-AMP synthase, and IFN-γ-inducible protein 16, all initiate immune signaling after recognition of a PAMP. PRR family-specific adaptor proteins such as mitochondrial antiviral signaling protein and stimulator of IFN genes relay these immune signals. For a virus to successfully infect the host cell, it must avoid detection in any way possible.

Since PRRs are located mainly in the cytoplasm and nucleus, the general sites of viral replication, it is no surprise that an immune escape strategy would be compartmentalizing viral genetic material. The formation of viral replication compartments by a diversity of viruses is known. For example, the Dengue virus replicates in the endoplasmic reticulum (ER). The hepatitis C virus (HCV) forms membranous webs in the ER, while the influenza A viruses (IAVs) mask their RNA genome in the cytoplasm and relocate it into the nucleus, all avoiding early detection. Along with this line, viruses also employ a more active approach toward evading immunity. RLRs complete their signaling pathways by completing post-translational modifications, namely ubiquitylation and serine/threonine phosphorylation. Viral proteins such as IAVs NS1 interact with E3 ubiquitin ligases (TRIM25), impeding their homo-oligomerization and disrupting their enzymatic activity. As another example, HCV NS3-NS4A protease complex cleaves Riplet, another RLR ubiquitin ligase, blocking pathway continuity. Other viruses go as far as to directly remove the ubiquitylation from RIG-I through virus-encoded enzymes, such as papain-like protease from severe acute respiratory syndrome (SARS)-associated coronavirus (SARS-CoV) and leader proteinase from foot-and-mouth disease virus, among others. Other forms of evading RIG sensing reduce the concentration of a specific cellular microRNA (mRNA), increasing the expression of a host deubiquitylating enzyme (DUB) and inhibiting the activation of RIG-I. The enterovirus 71 protein 3C downregulates miR-526a, increasing DUB enzyme CYLD cellular concentration.^21–24

Like MHC I, viral proteins target most intracellular PRRs for degradation, sequestration, or relocalization through direct or indirect action. Viral proteins can modify most aspects of their host’s molecular immunology. Be it the removal of critical post-translational modifications of elemental proteins, the permanent alteration of pre or post-enzymatic interactors in the immune response signaling pathway, the displacement of crucial components or changes in their functional concentration, or the abuse of their recognition and the resulting immune response. Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), the causative agent of one of the most recent and impactful pandemics, exhibits immune evasion strategies focusing on host protein translation and the induction of antiviral response elements. Non-structural protein 1 (NSP1) from SARS-CoV-2, similar to NSP1 from SARS-CoV, suppresses host protein translation while also cleaving host mRNAs. Along with limiting the production of host proteins, NSP1 also suppresses ISGs by inhibiting STAT1 phosphorylation, thus controlling the interferon viral response. Most if not all NSPs from SARS-CoV-2 provide support when it comes to minimizing detection and elimination from host cells.^25–27

Viruses that establish chronic infections evade, limit, and use the immune response in their favor while also modifying cell survival and proliferation. HCV NS3 protein interacts with tribbles homolog 3 (TRIB3) to avoid ER stress-induced apoptosis of host cells. Similarly, while interacting with TRIB3, NS3 protein promotes cell growth and proliferation through TRIB3 interaction with the MAPK/ERK pathway.^28,29 Another pro-survival adaptation found in viruses is the capture of immunoglobulin (Ig) superfamily proteins from hosts. These glycoproteins exhibit various functions imperative for the immune response, such as cell-cell adhesion, cell surface recognition, cytoplasmic signal transduction, and even soluble factors by secretion or shedding. Viruses such as Kaposi’s sarcoma-associated herpesvirus (KSHV) encode a homolog of CD200 (vCD200), a co-inhibitory membrane protein found on a large variety of cell types such as epithelial, endothelial, and neuronal cells and lymphocytes. The binding of CD200 with its receptor, CD200R, hinders the activity of CD200R-bearing cells, downmodulating their functions. This KSHV protein, encoded by the K14 gene, shares 44% of the amino acid sequence in its terminal Ig domain with human CD200. K14 binds to CD200R, reducing the activation of various immune cells.³⁰ These are just a few examples of viruses playing with our immune system. From these examples, research focused on specific proteins from the complete viral proteome.

Antigen Presentation Evasion Strategies

Pathogen recognition commences through the innate response. For recognition, this process utilizes general or universal sequences found in most pathogens, which are elements termed PAMPs. Viral mutations tend to change these PAMPs, allowing the infection of host cells. The infected cells call for help through the presentation of non-self-proteins by MHC I and II. This elegant form of antigen presentation is part of the adaptive immune response by which pathogen-infected and irregular or malign cells are identified and destroyed. Viruses have adopted different hampered antigen presentation methods, allowing virus survival and propagation.

Two clear examples of viral proteins that inhibit MHC I antigen presentation are those encoded by herpesviruses and the human cytomegalovirus (HCMV). These proteins interact at different levels of the antigen presentation cascade, impeding the further processing of antigens. These proteins, one from herpes simplex virus (HSV) and the other from HCMV, target the transporter associated with antigen processing (TAP) complex. TAP is necessary to transport antigens from the cytoplasm into the endoplasmic reticulum. The HSV ICP47 protein binds directly to TAP, inhibiting further peptide binding with its 10- to 1000-fold greater affinity for TAP’s peptide-binding site. It does not translocate like any other peptide and does not stimulate ATP hydrolysis or conformational changes in TAP. An HCMV protein, US6, also binds to TAP but functions differently. US6 does not block peptide binding but instead inhibits ATP binding (apparently through an indirect conformational change) by TAP and, thus, conformational changes that allow peptide translocation. Two other HCMV proteins, US2 and US11, disrupt the completion of MHC I molecules by promoting the degradation of one of its chains. On a similar note, adenoviral protein E19 inhibits MHC I trafficking by blocking the final binding of MHC I with TAP for antigen presentation. Thus, the MHC I molecule does not mature and is not successfully processed.^28,31,32

Viral Strategies That Modify Leukocyte (Lymphocyte) Chemotaxis

Complex biological systems depend on cellular mobility to relay signals, receiving or sending a message or completing a task. In adaptive immunity, antigen presentation, naive T-cell activation, T-cell homing to the afflicted site, and efficient distribution of effector cell functions require cell migration. Thus, it is unsurprising that viruses have exapted different means to interrupt or change this relay of information for cellular migration. Murphy³³ described that viral chemokine mimicry takes on various forms with mainly two general outcomes: lymphocyte retardant or attractant. The synthesis of chemokine antagonists, scavenging decoy receptors, or secreted chemokine scavengers benefits viral pathogenesis differently in a virus-dependent manner. A thoroughly studied example is the human immunodeficiency virus (HIV-1) envelope glycoprotein gp120. This protein participates in HIV immune cell recruitment, infection, and depletion. HIV also couples the expression of its proteins to that of C-X-C chemokine receptor-4 (CXCR4), facilitating cell migration.

This co-expression would increase viral fitness in dormancy and active infection scenarios by linking viral transcription to the expression of migration markers, such as CXCR4. In another example, the human papillomavirus (HPV) downregulates CXCL14 through its E7 oncoprotein, reducing the chemotaxis of different immune cells, such as lymphocytes, DCs, and NKs.^34–41 Also, the HCMV G protein-coupled receptor, US28, scavenges the RANTES (regulated upon activation, normal T cell-expressed and secreted) chemokine, limiting leukocyte recruitment.^42–46 HCV core protein (HCVc) plays a vital role in maintaining infection through modulation of the Th1/Th2 balance⁴⁷ and increasing Treg population numbers and their suppressor functions. HCVc increases T-cell differentiation toward the CD4, CD25, Foxp3, interleukin (IL)-10, and TGF-β Treg profiles and inhibits IL-2 production and the proliferation of bystander T cells. Aside from increasing Treg number and function, HCVc also sequesters Tregs in the inflamed liver by hampering CCR7 expression, a receptor involved in the chemotaxis, maturation, and activation of immune cells.^48,49

Applications

How viruses countermeasure host immunity has been an area of interest ever since the discovery of viral particles by Dmitri Ivanovsky⁵⁰ and Martinus Beijerinck.⁵¹ For researchers, to grasp the viral ideal of taming the immune response while retaining cellular function and continuity is to speak of an area defined as viral immunoprospecting. The potential applications of viral immune modulators, specifically those that drive cellular activity and differentiation, make this field seem tantalizing but, at the same time, promising.

Potential applications for immune system modulating viral proteins (ISMVPs) incline onto autoimmunity. From celiac disease to neurodegenerative autoimmune diseases such as multiple sclerosis (MS), viral immunomodulators could be directed to control and limit the damage caused by these pathologies.⁵² In MS, autoreactive CD4+ T cells recognize and orchestrate the immune response against components of the myelin sheath, the insulating lipid-rich layer covering axons of peripheral and central nervous system (PNS and CNS, respectively) cells. Upon recognition, CD4+ T cells release IFN-γ and tumor necrosis factor-alpha (TNF-α), activating macrophages and B cells. The activated cells, in turn, promote local inflammation and subsequent destruction of myelin-producing cells, predominantly those of the CNS (Schwann cells in PNS; oligodendrocytes in CNS). The outcome, in general, is progressive axonal loss and brain atrophy. ISMVP application in MS might reduce the IFN-γ and TNF-α response or limit CD4+ T-cell activation and differentiation. Using viral analogs that compete for activation receptors or hindering chemotaxis through the blood-brain barrier would limit macrophage and B-cell activation.^53,54 As in MS, CD4+ T cells in celiac disease activate cellular immune responses with otherwise innocuous peptides. Th priming activates inflammatory responses and antibody production, destroying intestinal epithelia.^55–57 Celiac disease pathogenesis could be constrained through the administration of ISMVP, reducing the immune response against gluten and self-peptides and limiting consequent damage to intestinal villi.

Apart from autoimmunity, viral proteins seem to function even better than mammalian proteins when it comes to cutaneous wound healing in a full-thickness murine skin wound model. Research on the orf virus (OV) vascular endothelial growth factor-E and OVIL-10 proved increased skin repair and improved scar quality over its mammalian variants. These viral proteins promoted wound re-epithelialization and re-vascularization along with the suppression of inflammation and M2 macrophage retention for improved blood vessel stabilization and collagen remodeling.⁵⁸ These findings support individual or combinatorial use of viral proteins in biomedical experimentation to promote their use as human therapeutics. Research on an experimental autoimmune retinopathy mouse model shows a premium example of the modular applications of viral therapeutics. In this investigation, the intravitreal injection of adeno-associated virus (AAV) vectors for delivering the myxoma virus gene M013 induced retina protection from inflammatory damage and immune cell infiltration, characteristic of the disease model. This gene therapy approach resulted in a lower clinical score (an indicator of retinal damage) and autoimmune protection by reducing C3 and IL-17A gene expression. The researchers modified the M013 protein by adding a secretion signal (Igκ) and a cell-penetrating signal (HIV-1 Tat-peptide).⁵⁹

Not only can these viral immunomodulatory molecules be adapted, but they can also serve as enhancers for existing therapeutics. Etanercept (ETN) is a TNF-α and TNF-β inhibitor with dual p75 TNF receptors bound to an IgG fragment crystallizable region (Fc). Its general application is straightforward: antagonistic capture of soluble TNF to limit the inflammatory response. Various groups of viruses, such as the poxviruses, produce a set of proteins named viral TNF receptors. These viral receptors fall into four protein categories: cytokine response modifier B (CrmB), CrmC, CrmD, and CrmE. Of these four proteins, CrmB and CrmD also include a chemokine-binding domain termed the smallpox virus-encoded chemokine receptor (SECRET). The SECRET domain shows inhibition of chemokine-induced cell migration. The combination of these blocking activities improved virulence and control of local inflammation, improving viral fitness.⁶⁰ Inspired by this, researchers modified the ETN compound to include a SECRET domain for an enhanced effect on the reduction of rheumatoid arthritis (RA) symptoms in the collagen-induced arthritis murine model.⁶¹ Through both activities, TNF and chemokine blocking, the resulting novel therapeutic required half the dose of its unmodified version, demonstrating higher efficiency in reducing the clinical scores in the RA mouse model.

Viral proteins are not exempt from the constant search for cancer therapeutics. Oncolytic viruses are extensively studied, with some cases of their therapeutic application being government-approved.⁶² Despite this, the use of viral proteins as anticancer agents remains in the early stage. A study employing the matrix (M) protein of the Peste des petits ruminants virus showed the induction of apoptosis in colorectal cancer cells when transfected with the M gene. Its hypothesized mode of action is the upregulation of genes, such as Bax, p53, and Caspase-9 through BH3-like motifs.⁶³ In a comprehensive review, Manocha et al.⁶⁴ discussed the proposed modes of action for the extensively studied viral proteins that carry anticancer potential. From the parvovirus NS1 with its protein kinase C post-translational modification requirement for the DNA damage response through checkpoint kinase 2 recruitment for ataxia-telangiectasia mutated phosphorylation (promoting cell cycle arrest), all the way to sindbis virus glycoproteins E1 and E2 inducing caspase-8-dependent apoptosis mediated by Bad, the application of viral proteins for the treatment of specific cancers is full of potential.

A premium example of the modular applications of viral therapeutics was presented in an experimental autoimmune retinopathy mouse model. In this investigation, the intravitreal injection of AAV vectors for the delivery of the myxoma virus gene M013 induced retina protection from the inflammatory damage and immune cell infiltration, characteristic of the disease model. This gene therapy therapeutic approach resulted in a lower clinical score (an indicator of retinal damage) and autoimmune protection. The researchers modified the M013 protein by adding a secretion signal (Igκ HIV-Tat region) for cell penetration. According to Felix et al.,⁶⁵ there were only two viral proteins in clinical trials for their immunomodulatory activity. Myxoma virus serine proteinase inhibitor 1 (Serp1) and a similar molecule, VT-111a, are being tested to reduce inflammatory cell activation, monocyte infiltration, and plaque increase in arterial trauma. Mouse model experiments of these and other immunomodulatory viral molecules demonstrated successful amelioration of disease.

Additionally, an initial screening for patents through the United States Patent and Trademark Office (USPTO) revealed a few inventions regarding viral molecules as immunomodulators. More abundant patents included the employment of viruses or their proteins as vaccines and enhancers. According to the USPTO, as for the immune modulation patents found, one of them uses the E2 glycoprotein from GB virus C as a treatment for pathogenic T-cell activation, namely inflammatory processes (U.S. Pat. No. 9,611,301), that is one patent application for viral immunomodulators out of approximately 600,000 yearly applications. This field has more than enough room for investigation and application. Finally, this search brings to mind previous attempts at placing viruses under the therapeutic spotlight. Researchers attempted to use bacteriophages as an antibiotic treatment, which became known as phage therapy. Unfortunately, this was just before the development of conventional antibiotics, such as penicillin, which wholly overshadowed phage therapy. Phage therapy could arise from slumber in an age of antibiotic resistance and super bacteria.⁴⁹ Throughout this review, we have described a variety of means for establishing infection and virus survival through immune evasion and modification. The use of these strategies, as of yet fully elucidated, might prove significant for manipulating immune states in target scenarios. Thus, there is an expected increase in research efforts and funding for viral immunoprospecting when government interest peaks in this interdisciplinary area with fantastic potential.

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Cite this article as:
Avila KWLD. Viral Molecules as Immunomodulators of T Lymphocyte Effect. Premier Journal of Immunology 2024:1;100002

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