The role of IFN-γ production during retroviral infections: an important cytokine involved in chronic inflammation and pathogenesis

ABSTRACT

Interferon-gamma (IFN-γ) plays a crucial role in viral infections by preventing viral replication and in the promotion of innate and adaptive immune responses. However, IFN-gamma can exert distinct effects in different persistent viral infections. The long-term overproduction of IFN-γ in retroviral infections, such as the human immunodeficiency virus (HIV), human T-lymphotropic virus type 1 (HTLV-1), and human endogenous retroviruses (HERVs), resulting in inflammation, may cause neuronal damage. This review is provocative about the role of IFN-γ during persistent retroviral infections and its relationship with the causation of some neurological disorders that are important for public health.

Retroviruses; HIV; HTLV-1; HERVs; Interferon-γ; Immune regulation

INTRODUCTION

Interferons (IFN) are a group of cytokines that induce the production of antiviral factors during viral infections. IFN-γ belongs to IFN type 2; its genes are located on chromosome 12, and the gene (IFNGR1) encodes the ligand-binding chain (alpha) of the heterodimeric gamma interferon receptor, which is found in macrophages ¹ . It induces the immunoregulation for the recognition of the antiviral and antitumor antigens ² ; it also stimulates T cell differentiation for the Th1 type response and clonal expansion, capable of acting in an autocrine and paracrine way, and the overexpression of IFNGR can induce pro-apoptotic phenotypes ³ .

Interferon-γ is secreted by B lymphocytes, Natural Killer (NK) cells, Natural Killer T lymphocytes (NKT), and antigen-presenting cells (APCs), resulting in inflammation and cellular recruitment ⁴ . This cytokine can interfere with viral replication ⁵ by activating the stimulated interferon genes, which induce the production of antiviral factors such as APOBEC-3G, TRIM5 alpha, MIP-1 alpha, and MIP-1 ⁶ . IFN-γ signalling activates the antigen-presenting cells (APCs) to upregulate the expressions of cytokines (IL‐12 and IL‐18) and CD86 costimulatory molecule that enhances the Th1 differentiation and cytotoxic T lymphocyte (CTL) function ⁷ , ⁸ . Therefore, IFN-γ is related to the class I main histocompatibility complex (MHC) and to the presentation of class II antigens; it also controls the differentiation of naive TCD4 cells into Th1 effector ⁹ . Those events mediate cellular immunity against intracellular agents. On the other hand, excess IFN-γ is related to chronic inflammatory and autoimmune diseases, such as multiple sclerosis and diabetes mellitus ⁹ - ¹¹ .

The IFN-γ is antagonistic to the production of immunosuppressive and anti-inflammatory interleukins, such as IL-10, and is directly responsible for down modulating the presentation of antigens by MHC class II, during the virus immune response in general. There is a lack of this regulatory mechanism and constant influence of the IL-2 ⁸ , ¹² and no limitation of the intensity of inflammatory response ⁸ , ¹³ . IFN-γ and IL-2 play a crucial role in the replication of host cells and may be a biomarker to monitor disease progression in infections ⁶ , ¹⁴ . This chronic overexpression of IFN-γ in different tissues can initiate several inflammatory disorders and excessive damage to tissues. This review intends to raise and analyze the information regarding the role of IFN-γ in persistent viral infections, particularly human retroviral infections with epidemiological importance ¹⁵ .

MATERIALS AND METHODS

The bibliographic research reported here followed some criteria for surveying, selecting and analysing the literature, as described below.

Sources for obtaining the information

The NCBI Pubmed electronic database was used for result retrieval. The searched terms such as Retroviruses; HIV; HTLV-1; HERVs; Interferon-γ (INF-γ) were adapted in order to meet the specific demands of the database. The latest search update was conducted on December 31, 2021.

After obtaining the articles that addressed the topic, texts were selected based on the content of their abstracts which reflected the objective outlined in the present review. Among all, 60 articles that met the thematic criterion were obtained and 14 of them discussed the role of the immune response and role of IFN-γ; 17 discussed the role of IFN-γ and HTLV-1 infection; 21 texts addressed the role of IFN-γ and HIV infection; and 13 highlighted the role of IFN-γ and HERV; some of them were included in more than one category.

Eligibility criteria

Cross‐sectional and review studies; the role of IFN-γ and HTLV-1, HIV and HERV infection; English language.

Exclusion criteria

Were excluded: Abstracts and conference proceedings, study protocols, editorials or commentaries, and letters to the editors not including any original data; co‐infection studies in an already known infected population; and not in the English language.

Reading and analysis of texts

We performed an analytical and comparative reading of the information obtained. The reading had two phases: (a) recognition reading and analysis of the content of each manuscript; (b) new reading in order to punctuate the relevant aspects about the role of IFN-γ and retroviruses infection.

The role of IFN-γ was firstly characterised, then followed the identification of the interferon-gamma response pathways and retrovirus infections. Thereafter, important data about the topic in general were evaluated. At the end, the possible mechanisms involved in retrovirus infection and stimulated by IFN-γ were identified. The following is the result of the survey and the bibliographic analysis performed with a view to systematise the knowledge about IFN-γ and retrovirus infection in the form of a literature review.

Interferon-gamma (IFN-γ) and its role in HTLV-1 infection

The Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus associated with several chronic inflammatory diseases such as uveitis, polymyositis, arthritis, alveolitis, infective dermatitis as well as some types of skin lesions, susceptibility to some opportunistic infections, and the HTLV-1 associated myelopathy (HAM) ¹⁶ , ¹⁷ .

HAM is potentially considered an immune-mediated disease, mainly due to the increase of cytokines and chemokines, and it stands out for the elevation of IFN-γ levels ¹⁸ , ¹⁹ . The production of IFN-gamma by CD8+ T cells is considerable in the central nervous system (CNS) due to the volume of cells expressing MHC class I antigens; it is also related to MHC class II involved in the production of IFN-γ ⁶ , ²⁰ . Therefore, the spontaneous IFN-γ production is more likely due to TAX activation over certain genes in the hosted cells ¹⁴ , ²¹ ( Figure 1 ).

Figure 1
Hypothesis of neuroinflammation process during HTLV-1 infection: 1) Activation of inflammation process; 2) T-cell proliferation; 3) Migratory process of infected T cells; 4) Pro-inflammatory cytokines and chemokines secreted during the neurodegeneration process. This inflammatory process will induce the release of cytokines in the spinal cord (thoracic segment). Initially, there is a proinflammatory local involvement, driven mainly due to IFN-gamma. Over a few years, this process is ongoing and chronic with the outcome being degenerative damage to the myelin membrane.

Some genes are over-expressed in the white blood cells of patients with HAM (HTLV-1-associated myelopathy), but not in asymptomatic HTLV-1 carriers or patients with the disease clinically similar to multiple sclerosis ²² , ²³ . The expression of these genes is induced by interferons, usually beneficial to the host protection, but it can also cause inflammation ²⁰ , ²² . It was noted that interferons do not efficiently suppress HTLV-1 protein expression in vitro and do not control chronic HTLV-1 infection, but instead contribute to the development of HAM ²⁴ . In addition, disorders of the p53 signalling pathway are hallmarks of HTLV-1 infection ²⁵ .

In contrast, a subset of IFN-stimulated genes is overexpressed in HAM cases but not in asymptomatic carriers and patients with a similar disease like multiple sclerosis ²³ . The IFN-inducible signature was present in all circulating leukocytes and its intensity is correlated with the clinical severity of HAM, where T and B cells from HAM cases were primed to respond strongly to stimulation with exogenous IFN ²² . However, while the type I IFN suppressed expression of the HTLV-1 structural protein Gag, it failed to suppress the highly immunogenic viral transcriptional transactivator Tax ²⁶ . Taken altogether, the overexpression of a subset of IFN-stimulated genes in chronic HTLV-1 infection does not constitute an efficient host response, but instead contributes to the development of HAM ²⁷ .

HTLV-1 can induce the infected cells to migrate, a property linked to cytoskeleton reorganisation induced by the viral Tax protein, the “virological synapse” (VS) promoting direct transmission based on cell-cell contacts ⁵ . Viral proteins of HTLV-1, such as Tax, can activate various signal pathways including the NF-κB and AP-1 pathways ¹⁸ . The major histocompatibility complex class I (MHC-I) antigen presentation pathway plays a central role in the development of host immunity against pathogens, where MHC-I molecules are expressed on the surface of all nucleated cells and present peptides to the TCRs of cytotoxic T lymphocytes ²⁰ . Effector CD8+ T-cells specifically recognize viral peptides via the TCR to destroy infected cells. Consequently, many viruses have evolved proteins whose main function is to interfere with this pathway ²⁸ .

The inflammatory process activated by HTLV-1 could be related to anatomical characteristics of the lumbar thoracic medulla due to the angulation of the radicular thoracic arteries and the Adamkiewicz-surge artery, causing local inflammation due to the production of cytokines, mainly an overproduction of IFN-γ ( Figure 1 ) ²⁷ , ²⁹ . One study found the production of a significant range of interferon levels (p=0.0001) in an asymptomatic patient (ASY) compared with patients who have HTLV-associated myelopathy (HAM) and (0.0009) in an asymptomatic patient (ASY) vs patients that did not have a complete framework for classification as HAM, and was named Intermediate Syndrome (SI), even as a very early phase of HAM ³⁰ . This shows that IFN-γ can be the pillar for a prognostic marker, as well as an indicator for anti-inflammatory treatment, as recommended in the last International Retroviral Association (IRVA) guideline ³¹ .

In summary, HTLV-1 leads to dysregulation of the immune system. Several studies have reported interferon-gamma as a central mediator of inflammation in patients with neurological damage associated with HTLV-1 ¹⁶ . Different immunological aspects are involved in virus/host interaction, and the way this interaction develops will determine whether the patient will be asymptomatic or afflicted with some condition, such as HAM ²⁰ . In this sense, IFN can be a potential marker to predict early disease development, since HAM is an immune-mediated disease, and may be of greater prognostic value when compared to HTLV-1 proviral load ¹⁴ . The immune response during viral infection is one of the important parameters that can determine the degree of infection. There is currently no cure for HTLV, however, partially blocking the production/action of IFN can be a palliative strategy for patient disease management ³¹ . The drugs currently used in clinical practice, for example, corticosteroids, can temporarily alleviate the pain that patients feel but are not effective for preventing long-term neurological damage ³¹ .

Role of the IFN-γ levels among HIV-1-infected subjects

Human immunodeficiency virus (HIV) is also a retrovirus, but unlike HTLV-1 it leads to the progressive loss of cells, resulting in Acquired Immunodeficiency Syndrome (AIDS). In this infection, there is a high production of pro-inflammatory cytokines, which in turn trigger apoptosis; they are important factors for modulating HIV-1 infection and in the replication rate of the virus during disease progression ³² .

Among those pro-inflammatory cytokines, the interferons produced during viral infections act on T and B lymphocytes, natural killer cells (NK), and phagocytic cells. They play a crucial role in the prevention of early replication from binding IFN-γ to its IFNGR-1 and IFNGR-2 ³² , triggering intracellular signalling to induce apoptosis of the infected cells, and regulating post-transcription and translation processes. This recognition could help in the development of new therapies to prevent infection and regulate innate and acquired immunity, controlling the spread of HIV in the early stages of infection ³³ .

People living with HIV (PLWH) can also have neurological symptoms. The virus can cross the blood-brain barrier during the acute phase, with the migration of infected monocytes from the bloodstream into the CNS and infect neighbouring cells, such as microglia and astrocytes ³⁴ . The antiviral cytokines present in the brain during infection control the viral replication in the CNS ³⁵ . In contrast, IFN-γ plays a protective role in uninfected children of mothers with HIV-1 ³⁶ , who have a higher concentration of IFN-γ and IL-10 than infected children. Exposure in the uterus to HIV-1 may increase the amount of IL-10 in the umbilical cord that is associated with protection against perinatal infection ³⁶ .

An interesting study on patients receiving interferon-alpha (IFN-α) therapy and in systemic lupus erythematosus patients demonstrated that elevated CSF levels of IFN-α are associated with cognitive dysfunction ³⁷ . In this direction, another manuscript observed that these high productions were significantly elevated in the CSF of PLWH with dementia compared to those without this diagnostic compared to controls, suggesting that the significant amounts of this protein ³⁸ . This detection in the CSF of HAND cases is derived from intrinsic brain cells such as macrophages and astrocytes. The increased local production of IFN-γ during HIV infection may contribute, directly or indirectly, to the pathogenesis of HIV-associated dementia (HAD) ³⁹ ( Figure 2 ).

Figure 2
Role of IFN secretion during HIV-1 infection. The presence of HIV RNA in endosomes activates Toll-like receptors, thus activating the NF-kappa beta pathway. The production of IFN-gamma promotes the JAK-STAT activation and consequently signalization of interferon-stimulated genes. After that, antiviral factors such as APOBEC, and TRIM-5alpha are produced.

On the other hand, there is evidence that the deficit of the signal transducer and activator of transcription 5 (STAT5) in HIV-infected patients can be restored with antiretroviral therapy ⁴⁰ , ⁴¹ . This is evident with the characterization of those transcription factors in the population and their correlation with the treatment and genotyping of the virus; some genes in the HIV-1 envelope are associated with resistance to IFN-γ function, resulting in greater infectivity due to the possibility of replication of viral particles ⁴⁰ .

The difficulty in assessing the real contribution of serum IFN-γ levels in PLWH stems from their antagonistic role, acting both as an inflammatory cytokine and as an enhancer of antiviral immunity ⁴² . During the acute stage of HIV-1 infection, the host immune system mounts an inflammatory response resulting in a cytokine storm ³⁷ . If not appropriately controlled, it enhances HIV-1 infection and may cause a higher viral set point before T cell immunity can control the HIV-1 load. Remarkably, low levels of IFN-γ are detected throughout HIV-1 infection, correlating with persistent HIV-1 replication ⁴³ . Furthermore, many of the HIV-1 proteins can directly stimulate T cells to produce IFN-γ, leading to chronic immune activation and ultimately to the exhaustion of the immune system and waste of IFN-γ production. However, IFN-γ therapy does not affect HIV-1 load or AIDS progression whereas ART has a dramatic effect on both, even if long-term ART does not completely restore the immune responses ⁴⁴ . Hence, IFN-γ may still play an important role as a product of HIV-specific polyfunctional CD4+ T cells, which may serve to enhance the anti-HIV antibody production as well as CTLs against HIV-1 infection ⁴⁴ .

HIV proteins are found in the central nervous system of patients progressing to HIV-associated neurocognitive disorder (HAND), along with high IFN-γ levels. Those HIV proteins lead to high activation of the JAK/STAT1 pathway that regulates the inflammation and apoptotic signalling associated with neuronal damage ⁴⁵ . Most HIV patients remain asymptomatic for years, albeit up to 60% of them present some degree of neurological disorder. Among those neuropsychiatric deficiencies, HIV-associated dementia (HAD) is the most severe form with an average survival of only six months after the onset of symptoms ⁴⁵ . Antiretrovirals are not able to control HIV replication in the CNS, but an early start of antiretroviral treatment may decrease the incidence of neurological diseases ⁴⁶ .

Neurons are not killed directly by a viral infection, but viral proteins induce the production of cytokines such as IFN-γ, TNF-α, and IL-1β which are neurotoxic. A study found that the JAK/STAT pathway, a key regulator of inflammatory and apoptotic signalling, is elevated in HIV-1-infected brains progressing to HAND ³⁴ . This pathway can be inhibited by the epigallocatechin-3-gallate (EGCG) present in green tea, resulting in a decrease of inflammatory cytokines and the consequent mitigation of neuronal damage in the cortical regions of mouse brains, as compared to controls ⁴⁵ . These observations suggest the use of IFN-γ for monitoring patients that tend to progress to HAND and it can be an important therapeutic target, as an adjunct to ART, to prevent it. Immunological pathways that activate the production of pro-inflammatory cytokines and chemokines should be investigated in order to help in the development of a treatment strategy to prevent patients from becoming dependent ³⁴ , ⁴⁶ .

Some people remain negative for HIV infection despite having unprotected sex with viremic HIV-positive patients. They show a higher production of IFN-γ in CD3-CD56 bright (NK) and CD3 ⁺ /CD56 ⁺ (TNK) cells in their plasma, which can be their protector factor ⁴⁷ . In this sense, approximately 30% of HIV-positive patients, treated with ART for four years, have high levels of IFN-γ in their plasma and low amounts of circulating CD4 ⁺ T lymphocytes ⁴² . Since HAND may occur in up to half of the HIV-positive individuals, even with cART, adjunctive therapies are needed ⁴⁸ .

Human endogenous retroviruses (HERVs) as regulators of neuroinflammation

Most of the human endogenous retroviruses (HERVs) are not capable of encoding functional proteins (junk DNA). They are considered remnants of exogenous retrovirus, since they have 5’LTR, GAG, POL, ENV, and 3’LTR ⁴⁹ , ⁵⁰ . HERVs have retroviral envelopes that are composed of glycoproteins, such as syncytin-1, that bind to ASCT1 and ASCT2, located in neurons and glia, responsible for modulating the neurotoxic and neurotrophic effects ⁵⁰ . The overexpression in astrocytes increases pro-inflammatory cytokines responsible for causing neuroinflammation, neurodegeneration, and stress response of the endoplasmic reticulum, being harmful to the oligodendrocytes involved in the formation of myelin. The regulatory factor of interferon 1 (IRF1) and NF-κB can trigger the expression of HERV-K through the response stimulated by interferon in neurons of the motor cortex, suggesting the potential role of HERVs in the mediation of inflammation in neuropsychological disorders ⁴⁹ , ⁵⁰ .

Despite the association of HERVs with neuroinflammation, there are few studies in the literature that report the influence of HERVs in the production of interferon-gamma. In this sense, the greater exposure to IFN gamma seems to generate a positive feedback loop for the activation of STAT1 and to induce the expression of CXCL10, IFN-β, PD-L1, and ERVs, in cases of mesenchymal tumours with high expression of AXL/MET and low levels of EZH2 ⁵¹ . As for HTLV infection and the onset of HAM, no relationship was found between the expression of HERVs and the cause of this disease ⁵² . In addition, IL-12 produced by macrophages and dendritic cells promotes the differentiation of T lymphocytes into Th1 and the activation of NK cells, both responsible for secreting interferon-γ (IFN-γ), which acts in the activation of macrophages and lymphocytes ⁵² .

Thousands of endogenous retroviruses (ERV), viral fossils of ancient germ line infections, reside within the human genome. Evidence of ERV activity has been observed widely in both health and disease ⁵³ . While this is most often cited as a bystander effect of cell culture or disease states, it is unclear which signals control ERV transcription. Bioinformatic analysis suggested that the viral promoter of ERVK is responsive to inflammatory transcription factors ⁵⁴ . For example, ERVK upregulation in amyotrophic lateral sclerosis (ALS) is the presence of functional interferon-stimulated response elements (ISREs) in the viral promoter ⁵⁵ . Transcription factor overexpression assays revealed independent and synergistic upregulation of ERVK by interferon regulatory factor 1 (IRF1) and NF-κB isoforms. Thus, neuroinflammation is a key trigger of ERVK provirus reactivation in ALS. It has been well established that the inflammatory signalling pathways in ALS converge at NF-κB to promote neuronal damage ⁵⁵ . Therefore, quenching ERVK activity through antiretroviral or immunomodulatory regimens may hinder virus-mediated neuropathology and improve the symptoms of ALS or other ERVK-associated diseases, such as HAND mechanisms ⁵⁶ .

Endogenous retrovirus can also be related to the incidence of HAND, since HIV may activate two human endogenous retroviruses. The human endogenous retrovirus (HERV)-W is associated with multiple sclerosis (MSRV) ⁵⁷ . HERV-k II is highly expressed in human neurons, especially in seropositive people, due to the release of HIV proteins such as Vpr, Tat, Env, and the proliferation of glial infected cells and leukocytes ⁵⁸ ( Figure 3 ). This product is toxic to neurons in the long term, and when added to host susceptibility factors leads to enhanced inflammation, with a consequent increase of apoptosis and necrosis ⁵⁹ . On the other hand, the expression of HERV-K (II) in neural cells can also exert neuroprotective effects, as it prevents the neurotoxicity measured by HIV-1, and can exert adaptive effects in the pathophysiological stress ⁵⁸ .

Figure 3
Endogenous retrovirus expression in the central nervous system. The HERVs are expressed in several cell types. In astrocytes, regarding the viral chronic infection context, there is a major expression of the HERV proteins that, when added with inflammatory molecules, promote neuronal damage.

The introduction and integration of retroviruses in the chromosome of our genome are considered a final stage of parasitism and the hallmark of immunity evasion ⁶⁰ . There is a large number of endogenous viral sequences of different origins along the vertebrate genomes. Some of those sequences can still maintain viral characteristics, such as replication and the ability to activate innate and adaptive immune responses, which may or may not cause beneficial and/or pathogenic effects in humans ⁵⁷ .

In addition, viral sequences inherited by the germline that are part of our genome represent 5% of it and can act as restriction factors. ERV Gag proteins interfere with the exogenous retrovirus infection cycle, which consequently modulates the immune system cis-pro inflammatory regulators ⁶⁰ . These mechanisms can improve the levels of interferon, triggering the activation of T cells and also suppressing the immunological effects on the immune system ⁶⁰ .

Limitations of the study

The current study has several major limitations since it was not a systematic review. Hence, the results of studies using bibliographic research methods need to be interpreted with caution, and the reliability and validity issues should be taken into account when interpreting their results.

CONCLUSION

The IFN-γ can be considered a double-edged sword, therefore it is essential to understand its biological functions in the face of infections. Different actions are at play to achieve a balance between control of infections with retroviruses and the host. As such, understanding the host-pathogen interaction is essential for the development of drugs and viral therapeutic measures aimed at patients, to achieve cures and prevent progression to life-threatening diseases. These viruses are broadly disseminated worldwide andthe neurological outcomes should be of concern as nowadays it has epidemiological importance.

ACKNOWLEDGMENTS

We dedicate this work to all our patients over the last 20 years and to medical fellows, psychologists, nurses, nutritionists, and ex-medical residents who cared for them.

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Publication Dates

• Publication in this collection
  30 Sept 2022
• Date of issue
  2022

History

• Received
  26 May 2022
• Accepted
  9 Aug 2022