‘This review examines the potential role of herpesvirus reactivation, specifically Epstein-Barr virus (EBV) and cytomegalovirus (CMV), in the pathogenesis of PASC [Post-Acute Sequelae of SARS-CoV-2 infection].’

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‘Human herpesvirus reactivation and its potential role in the pathogenesis of post-acute sequelae of SARS-CoV-2 infection’.

© 2024 Gáspár et al / Springer Nature: GeroScience.

❦ Human herpesvirus reactivation and its potential role in the pathogenesis of post-acute sequelae of SARS-CoV-2 infection

By Gáspár et al / Springer Nature: GeroScience (29 Aug 2024)

[Abridged article: Please refer to original manuscript for full text. Link is provided below.]

✾ Abstract

‘The emergence of SARS-CoV-2 has precipitated a global pandemic with substantial long-term health implications, including the condition known as post-acute sequelae of SARS-CoV-2 infection (PASC), commonly referred to as Long COVID.

‘PASC is marked by persistent symptoms such as fatigue, neurological issues, and autonomic dysfunction that persist for months beyond the acute phase of COVID-19.

This review examines the potential role of herpesvirus reactivation, specifically Epstein-Barr virus (EBV) and cytomegalovirus (CMV), in the pathogenesis of PASC.’

Elevated antibody titers and specific T cell responses suggest recent herpesvirus reactivation in some PASC patients, although viremia is not consistently detected.

‘SARS-CoV-2 exhibits endothelial trophism, directly affecting the vascular endothelium and contributing to microvascular pathologies.

These pathologies are significant in PASC, where microvascular dysfunction may underlie various chronic symptoms.

Similarly, herpesviruses like CMV also exhibit endothelial trophism, which may exacerbate endothelial damage when reactivated.’

Evidence suggests that EBV and CMV reactivation could indirectly contribute to the immune dysregulation, immunosenescence, and autoimmune responses observed in PASC.

Additionally, EBV may play a role in the genesis of neurological symptoms through creating mitochondrial dysfunction, though direct confirmation remains elusive.

The reviewed evidence suggests that while herpesviruses may not play a direct role in the pathogenesis of PASC, their potential indirect effects, especially in the context of endothelial involvement, warrant further investigation.

✾ Introduction: Symptoms of PASC

Patients report various symptoms as part of PASC, including neurological symptoms (commonly referred to as “brain fog”), fatigue, sleep disturbances, memory disturbances, headaches, autonomic dysfunction such as postural orthostatic tachycardia syndrome (POTS), musculoskeletal pain, post-exertional malaise, chest pain, cough, loss of smell or taste, and anxiety.

✾ Introduction: Prevalence of PASC

Evaluating the prevalence of PASC is challenging due to heterogeneous definitions, symptomatology, and the lack of consensus.

Conservative estimates based on WHO data suggest that approximately 10–20% of individuals infected with SARS-CoV-2 subsequently develop this condition.

However, the prevalence may be significantly higher in certain populations, with studies indicating that close to two-thirds of COVID-19 survivors may develop PASC.

✾ Introduction: Potential mechanisms involved in the pathogenesis of PASC

The potential causes and pathophysiological mechanisms of PASC remain unknown, though several theories exist, including microvascular dysfunction, persisting low-grade neuroinflammation, mitochondrial damage and dysfunction, autoimmune processes, SARS-CoV-2 viral persistence, and immune activation, either individually or in combination.

✾ Introduction: Role of microvascular endothelial dysfunction

Microvascular dysfunction has emerged as a significant factor in the pathogenesis of neurological sequelae of COVID-19 and PASC.

The endothelial trophism of SARS-CoV-2 directly impacts the microvasculature, leading to widespread endothelial damage and inflammation.

This damage is often characterized by endothelial cell activation, microthrombosis, and increased vascular permeability, contributing to a range of long-term symptoms.

In patients with COVID-19, persistent endothelial dysfunction has been observed long after the acute phase of the infection.

✾ Introduction: Role of neuroinflammation

Emerging evidence suggests that persisting low-grade neuroinflammation plays a critical role in the pathogenesis of PASC.

Studies have shown that individuals with PASC often exhibit markers of on-going inflammation, which may underlie many of the neurological and cognitive symptoms associated with this condition.

✾ Introduction: Connection between microvascular endothelial dysfunction, neuroinflammation, and herpesvirus reactivation

A potential contributor to persistent neuroinflammation in PASC is the reactivation of latent herpesviruses, such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV).

Both EBV and CMV have known neurotropic and endothelial-tropic properties, allowing them to infect and persist in the central nervous system and the vascular endothelium.

Reactivation of these viruses under conditions of immune stress, such as during or after an acute SARS-CoV-2 infection, can exacerbate the inflammatory environment within the brain.

The presence of these viruses can trigger additional immune responses, further activating microglia and perpetuating the cycle of neuroinflammation.

Emerging evidence underscores the interconnected roles of herpesvirus infection/reactivation and microvascular endothelial dysfunction as well [84–91].

Reactivated EBV and CMV can infect endothelial cells and promote a pro-inflammatory state, thereby perpetuating the cycle of endothelial dysfunction and neuroinflammation.

This interplay between viral reactivation and endothelial damage may contribute to the persistence and severity of PASC symptoms.

This review aims to provide a comprehensive summary of the potential role of various herpesvirus infections in the pathogenesis of PASC, highlighting the complex interconnections between microvascular endothelial dysfunction, neuroinflammation, and viral reactivation.

Understanding these mechanisms is crucial for developing targeted therapeutic strategies to mitigate the long-term impacts of PASC.

✾ Background on herpesviruses and their reactivation

Herpesviridae is a large family of double-stranded DNA viruses that affect humans and animals.

Key members affecting only humans are divided into three subfamilies: alpha (herpes simplex virus type 1 and 2, and varicella-zoster virus), beta (CMV, human herpesvirus 6 [HHV-6], and human herpesvirus 7), and gamma (EBV and Kaposi’s sarcoma-associated herpesvirus/human herpesvirus 8).

Transmission occurs via direct contact, respiratory routes, or body fluids, with viral replication and assembly taking place within the host cell.

✾ Clinical phases of herpesvirus infection

Human herpesvirus infection is characterized by three distinct clinical phases: the acute phase, latent infection, and reactivation.

The acute phase involves continuous viral replication, viral assembly, and a cytolytic mechanism, during which the virus is released from the cell.

This phase primarily involves epithelial cells and is controlled by the adaptive immune system.

Subsequently, the virus enters a latent phase in specific cell types, with the viral genome present in the host cell nucleus without significant active replication.

✾ Biological mechanisms of latency

The latency phase of herpesvirus infection is a complex process that enables the virus to persist in the host for extended periods without causing active disease.

This phase is marked by the maintenance of the viral genome in a dormant state within host cells, where it evades the host immune system.

Several biological mechanisms contribute to the establishment and maintenance of viral latency.

Latency-associated transcripts (LATs) are non-coding RNAs expressed during the latent phase of herpesvirus infection.

These transcripts play a crucial role in maintaining latency by inhibiting apoptosis and modulating the host cell’s stress response, thereby ensuring the survival of infected cells and the viral genome.

The viral genome undergoes epigenetic modifications such as methylation and histone modification, which silence the expression of lytic genes and maintain the virus in a quiescent state.

These epigenetic changes prevent the reactivation of the virus under normal conditions but allow for quick reactivation when triggered by specific stimuli.

During latency, herpesviruses employ multiple strategies to evade the host immune system.

For example, they downregulate the expression of major histocompatibility complex (MHC) molecules on the surface of infected cells, reducing their recognition and destruction by cytotoxic T lymphocytes.

Additionally, latent viruses produce proteins that inhibit the presentation of viral antigens and the activation of immune responses.

Herpesviruses establish latency in specific cellular reservoirs that are less likely to be targeted by the immune system.

CMV primarily establishes latency in myeloid lineage cells, including monocytes, macrophages, and their CD34 + progenitor cells in the bone marrow.

During latent infection, the viral genome persists in these cells without producing infectious virions.

CMV can reactivate in response to immunosuppression or cellular differentiation, leading to viral replication and dissemination.

EBV primarily targets B lymphocytes for latency, especially memory B cells.

HHV-6 establishes latency in a variety of cell types, including monocytes, macrophages, and CD4 + T lymphocytes.

These cellular reservoirs provide a protected environment for the viruses, allowing them to evade immune surveillance and persist for the lifetime of the host.

During latent infection, some fraction of latently infected cells may still produce low levels of virions, which can activate a herpesvirus-specific T-cell response.

These herpesvirus-specific T cells can induce inflammatory responses at mucosal surfaces and become transiently activated during secondary infections, potentially modulating immune responses to other antigens.

Understanding the intricate mechanisms of herpesvirus latency is crucial for developing strategies to manage and treat herpesvirus-associated diseases, particularly in the context of co-infections such as SARS-CoV-2.

✾ Notes from the study.

❦ Epstein-Barr virus (EBV):

EBV is an oncogenic virus transmitted through close contact, replicating within the oropharyngeal epithelium and B cells.

In immunocompetent patients, primary infection manifests either asymptomatically or as the classic mononucleosis syndrome.

The innate immune system recognizes EBV antigens through various pattern recognition receptors, subsequently activating the adaptive immune system and eliciting a virus-specific immune response.

Reactivation of latent EBV can occur under immunocompromised conditions, acute stressors, or concurrent acute infections.

In most latent cells, the EBV genome is present without significant replication; however, some viral genes continue to be expressed, driving oncogenesis.

Proteins responsible for the cytolytic phase also play a role in driver mutations.

EBV is associated with various lymphoproliferative diseases (e.g., Hodgkin lymphoma, some non-Hodgkin lymphomas, Burkitt lymphoma) and epithelial cell malignancies (e.g., nasopharyngeal carcinoma).

Also, in HIV-associated lymphomas, especially primary central nervous system lymphomas EBV in malignant cells can be detected in approximately 40–100% of cases.

Additionally, EBV is linked to autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis, Sjögren’s syndrome, and multiple sclerosis.

The mechanisms and evidence behind the association between EBV and autoimmune diseases involve several interrelated processes.

Additionally, patients with SLE (systemic lupus erythematosus) often exhibit elevated levels of viral nucleic acids or EBV antigen titers, providing further evidence of the association.

Similar associations can be observed between multiple sclerosis (MS) and EBV infection.

Individuals infected with EBV have a 30-fold increased risk of developing MS compared with those who are EBV-negative.

A high EBV antibody titer following infection is a strong predictor for the development of MS.

❦ Cytomegalovirus (CMV):

CMV is a beta-herpesvirus that typically manifests asymptomatically or as mononucleosis syndrome.

Primary infection is usually self-limiting and requires only supportive care.

CMV seroprevalence increases with age, approaching nearly 100% in developing countries.

During primary infection, a robust immune response is generated, involving both the innate and adaptive immune systems.

The adaptive immune response includes the production of specific neutralizing antibodies and CD4 + and CD8 + T cells.

Despite the strong primary immune response, CMV establishes latency through immunomodulation.

After primary infection, CMV latency is predominantly established in myeloid cells and their CD34 + bone marrow progenitors, as well as in epithelial and mesenchymal cells.

During latency, no active virion production occurs; only latency-associated genes and proteins.

From latency, CMV reactivation can occur, either iatrogenically or due to medical conditions, leading to disseminated disease with multi-organ involvement.

Primary CMV infection can also occur congenitally.

During pregnancy, maternal infection may result from the reactivation of a latent virus or from reinfection through close contact with a susceptible individual.

Maternal infection leads to viremia, allowing the virus to spread transplacentally to the foetus.

Congenital CMV is the leading cause of congenital infections, in a long-term contributing to visual or sensorineural hearing impairment, intellectual disability, and cerebral palsy.

Studies on congenital CMV have demonstrated that almost all cell types in the central nervous system are susceptible to CMV infection, with astrocytes and the microvasculature system particularly supporting the entire replication process.

❦ Human herpesvirus 6 (HHV-6):

Human herpesvirus 6 encompasses two distinct viruses: HHV-6A and HHV-6B.

Similar to other herpesvirus infections, HHV-6 targets and replicates within a wide range of cells primarily targeting CD4 + T-cells.

Primary infection, which is generally a mild, self-limiting illness, occurs almost exclusively due to HHV-6B during the first 3 years of life.

Following primary infection, the virus establishes latency in the monocyte-macrophage system and T-cells.

Reactivation of HHV-6 can occur under various immunosuppressive conditions, most commonly associated with solid-organ or hematopoietic cell transplantation, leading to end-organ diseases such as myelosuppression, encephalitis, pneumonitis, and hepatitis.

HHV-6 is also linked to a range of neurological conditions, including febrile seizures, mesial temporal lobe epilepsy, and encephalitis, attributed to its neurotropic properties.

The virus exhibits neuroinvasive characteristics, activating oligodendrocytes and astrocytes, thereby creating a Th1-mediated proinflammatory state.

Additionally, HHV-6 binds to the CD46 receptor, contributing to an enhanced complement activation, decreased interleukin-10 production and increased interleukin-17 level, thereby promoting neuroinflammation and the development of neurological conditions.

HHV-6 has also been linked to myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS), although evidence remains inconclusive.

[Please refer to original manuscript for full text. Link provided below.]

✾ Herpesviruses and endothelial trophism

Herpesviruses, including CMV, EBV, and HHV-6, exhibit endothelial trophism, meaning they have a propensity to infect and persist in endothelial cells.

This endothelial infection plays a significant role in the pathogenesis and clinical manifestations of herpesvirus infections.

CMV is well-documented for its endothelial trophism.

The virus can infect and establish latency in endothelial cells, leading to various vascular pathologies.

CMV infection of endothelial cells induces a pro-inflammatory state characterized by the expression of adhesion molecules and the secretion of cytokines and chemokines, which can promote leukocyte adhesion and transmigration.

This inflammation contributes to the development of atherosclerosis, transplant vasculopathy, and other vascular diseases.

CMV infection was shown to cause endothelial dysfunction and potentially impair endothelial barrier function.

CMV infection likely also promotes the formation of microthrombi.

EBV also has the capability to infect endothelial cells. In endothelial cells, EBV can induce changes that promote endothelial dysfunction and inflammation and contribute to the pathogenesis of various vascular diseases.

HHV-6 is also known to infect endothelial cells.

HHV-6 infection in endothelial cells can lead to the production of pro-inflammatory cytokines and the upregulation of adhesion molecules, promoting an inflammatory response and leukocyte adhesion.

The endothelial trophism of these herpesviruses means that they can directly contribute to vascular inflammation and damage, which are central features in many of their associated diseases.

Reactivation of herpesviruses in endothelial cells is thought to contribute to the exacerbation of a range of pathologies, particularly in immunocompromised individuals.

✾ Risk factors for herpesvirus reactivation

Various risk factors can contribute to enhanced viral replication and gene expression, leading to the reactivation phase of herpesviruses.

These risk factors differ among Herpesviridae subfamilies but typically include oncohematological malignancies, steroid or other immunosuppressive treatments, chemotherapy, irradiation, local injury, other infections, UV light exposure, and hormonal imbalances.

Additionally, age-associated degradation of the immune system, particularly affecting cellular immunity, plays a significant role.

Immunosenescence refers to the functional decline of the immune system associated with aging, characterized by reduced responses to antigen stimuli and a decreased number of effective immune cells, increasing susceptibility to infections and auto-reactive pathways.

Age-related chronic low-grade inflammation creates a pro-inflammatory environment in various tissues, facilitating herpesvirus reactivation and contributing to low-level chronic inflammation, further exacerbating age-related immune mechanisms.

✾ Reactivation of herpesviruses in PASC

The reactivation of latent herpesviruses, such as EBV, CMV, and HHV-6, is a significant concern in patients with COVID-19 [82, 165–178] [180–182].

Several factors associated with COVID-19, including immune dysregulation, systemic inflammation, and direct viral interactions, can trigger the reactivation of these latent viruses.

COVID-19 is characterized by profound immune dysregulation [41], which can diminish the host’s ability to keep latent herpesviruses in check.

This weakened immune surveillance can lead to the reactivation of these viruses.

Studies have shown that severe SARS-CoV-2 infection can significantly suppress T-cell function [41], which is critical for controlling latent herpesvirus infections.

Increased production of inflammatory cytokines induced by SARS-CoV-2 infection can also contribute to herpesvirus reactivation.

SARS-CoV-2 may also directly influence the reactivation of latent herpesviruses through molecular interactions.

Additionally, the viral proteins of SARS-CoV-2 can interact with cellular pathways that regulate viral latency, thereby facilitating the reactivation of latent herpesviruses.

Reactivation of herpesviruses in the context of COVID-19 has significant clinical implications.

Patients experiencing reactivation of EBV, CMV, or HHV-6 can present with a range of symptoms that overlap with or exacerbate those of PASC, such as fatigue, cognitive impairment, and inflammatory conditions.

✾ Role of CMV reactivation in the pathogenesis of PASC

CMV has been proposed as an indirect contributor to the long-term symptoms of PASC by inducing immune alterations, thereby aggravating immune dysregulation.

CMV reactivation may play a role in neurocognitive dysfunction, brain fog, and musculoskeletal syndromes associated with PASC.

Although clinical trials have not demonstrated significant CMV viremia among PASC patients, elevated antibody titers suggesting viral reactivation are often present.

CMV exhibits significant endothelial trophism. The virus can infect and establish latency in endothelial cells, leading to chronic endothelial dysfunction.

Given the endothelial trophism of both SARS-CoV-2 and CMV, a plausible hypothesis is that the reactivation of CMV and/or other herpesviruses within endothelial cells may contribute to the pathogenesis of PASC.

This is particularly relevant given the emerging importance of microvascular impairments in the pathogenesis of PASC.

Reactivation of CMV in endothelial cells may potentially cause a range of microvascular pathologies, which are significant factors in the development of PASC.

Continuous viral presence and activity within endothelial cells can sustain a pro-inflammatory and pro-thrombotic state, contributing to on-going symptoms such as fatigue, brain fog, and cardiovascular issues.

CMV reactivation in endothelial cells can lead to the production of pro-inflammatory cytokines and chemokines, which enhance leukocyte adhesion and transmigration across the endothelial barrier.

This inflammatory cascade could result in neurovascular damage, contributing to persistent low-grade neuroinflammation and impaired regulation of cerebral blood flow, conditions commonly observed in PASC patients.

Moreover, CMV reactivation in the endothelial cells of the brain vasculature can compromise the integrity of the BBB.

This compromised BBB allows peripheral inflammatory mediators and immune cells to infiltrate the central nervous system, exacerbating neuroinflammation.

This exacerbated neuroinflammation is likely to contribute to neurocognitive symptoms such as brain fog and cognitive dysfunction.

Importantly, the endothelial involvement in herpesvirus reactivation is expected to mirror the pathophysiological mechanisms seen in chronic conditions like ME/CFS, which is also associated with viral infections and endothelial dysfunction.

The potential role of CMV reactivation in promoting these cerebromicrovascular and neurological abnormalities underscores the need for further studies to elucidate the exact mechanisms involved and to explore targeted therapeutic interventions.

Understanding the consequences of CMV’s endothelial trophism and its implications for CMV reactivation is crucial for developing effective treatments for PASC.

Further research is necessary to investigate the extent of CMV reactivation in endothelial cells and its direct contribution to the pathophysiology of PASC.

✾ Role of EBV reactivation in the pathogenesis of PASC

EBV reactivation has been implicated as a potential contributor to the pathogenesis of PASC [28, 40, 76, 79, 80, 81, 168, 172, 173, 178, 195, 196, 197, 198].

EBV viremia can occur among hospitalized, critically ill COVID-19 patients and may predict the development of PASC. Acute SARS-CoV-2 and EBV infections may interact under these circumstances.

The SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), promotes the Z transcriptional activator, enhancing latent EBV reactivation. EBV reactivation, in turn, increases ACE2 expression on epithelial cells, promoting SARS-CoV-2 viral entry [81].

The reactivation of EBV in the context of COVID-19 and PASC has significant clinical implications [198]. Recent studies have explored the link between EBV reactivation and PASC [40, 83, 118, 199].

It is hypothesized that EBV reactivation can lead to a range of symptoms that overlap with or exacerbate those of PASC, including fatigue, neurocognitive dysfunction, and autonomic disturbances.

EBV reactivation has been associated with neuroinflammation [116], which can contribute to the cognitive impairments observed in PASC patients.

Microglial activation, a hallmark of neuroinflammation, can be driven by EBV reactivation and may lead to synaptic dysfunction, neuronal injury, and impaired neurogenesis [116].

These effects can manifest as brain fog, memory disturbances, and reduced cognitive function, which are commonly reported in PASC patients.

EBV reactivation during acute SARS-CoV-2 infection can also contribute to PASC symptoms through promoting mitochondrial dysfunction [198].

✾ Role of HHV-6 reactivation in the pathogenesis of PASC

After primary infection, usually in early childhood, HHV-6 establishes lifelong latency in various cell types, including monocytes, macrophages, and CD4 + T lymphocytes.

Reactivation of HHV-6 under conditions of immune stress during or after an acute SARS-CoV-2 infection may significantly contribute to the pathogenesis of PASC [81, 82, 175, 177].

The ability of HHV-6 to infect endothelial cells and its neurotropic nature can have significant implications for PASC [148, 149, 150, 200].

Reactivation of HHV-6 in endothelial cells can potentially lead to endothelial dysfunction, contributing to microvascular impairments [200].

In the central nervous system, HHV-6 reactivation could potentially contribute to neuroinflammation and the neurocognitive symptoms observed in PASC.

The role of HHV-6 as driver in the pathogenesis of ME/CFS is increasingly recognized and continuously re-emerging in scientific research.

The high prevalence of active HHV-6 infection in ME/CFS patients, along with the concurrent increase in plasma proinflammatory cytokines and the correlation between active viral infection and PASC-like clinical symptoms of ME/CFS, underscores the necessity for in-depth study of herpesvirus reactivation in the context of PASC to better understand its contribution to the pathogenesis of the disease [190, 193, 194, 203].

This growing body of evidence highlights the importance of exploring the role of HHV-6 and other herpesviruses in general and their microvascular impact in particular, in driving the complex symptomatology seen in PASC.

Understanding these interactions is crucial for developing targeted interventions and improving patient outcomes.

✾ Conclusion and future direction for research

The precise pathogenesis of post-acute sequelae of SARS-CoV-2 infection remains undetermined, complicating efforts to develop effective treatments.

Numerous studies suggest that herpesvirus reactivation may contribute to PASC, although clinical trials have not consistently identified significantly elevated viremia levels.

Nonetheless, evidence indicates that herpesviruses, particularly CMV, EBV, and/or HHV-6, may play an indirect role through mechanisms such as microvascular endothelial dysfunction, BBB disruption, immune dysregulation, and/or the maintenance of low-grade chronic inflammation.

The direct infection of endothelial cells by SARS-CoV-2 and the potential reactivation of latent herpesviruses within these cells can contribute to the persistent vascular inflammation and dysfunction observed in PASC patients.

This endothelial damage can impair neurovascular coupling, disrupt the BBB, and promote a pro-inflammatory state, exacerbating the symptoms of PASC.

Additionally, elderly patients may be more affected by PASC due to age-related immunosenescence and impaired antiviral immune responses, which heighten their vulnerability to both SARS-CoV-2 and herpesvirus reactivation.

Further research is essential to elucidate the exact mechanisms by which these viruses interact and contribute to the pathogenesis of PASC.

Large-scale cohort studies and detailed mechanistic investigations are needed to confirm these findings and identify specific therapeutic targets.

Developing targeted therapeutic strategies, such as antiviral treatments and anti-inflammatory agents, could mitigate the long-term effects of PASC and improve the quality of life for affected individuals.’

✾ References

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📖 (29 Aug 2024 ~ Springer Nature: GeroScience) Human herpesvirus reactivation and its potential role in the pathogenesis of post-acute sequelae of SARS-CoV-2 infection ➤

© 2024 Gáspár et al / Springer Nature: GeroScience.

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