Childhood Stress – Herpes Simplex
A study published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS) indicates that a stressful early childhood history affects the long-term functioning of the immune system, specifically evidenced by a secretion of higher levels of herpes simplex virus (HSV)-antibodies into saliva.
Herpes simplex virus or cold sores in children are small blisters around the mouth caused by the herpes simplex virus. They are sometimes called fever blisters. The most common cause of cold sores is the virus called herpes simplex virus 1. The herpes simplex virus in a cold sore is contagious. The virus can also be spread to others 24 to 48 hours before the cold sore appears.
A child is more at risk for cold sores if they live with someone infected with the herpes simplex virus. Once a child is infected with the herpes simplex virus, the virus becomes inactive (dormant) for long periods of time. It can then become active at any time and cause cold sores again. The cold sores usually don’t last longer than a few days, or up to 2 weeks.
The link between psychological stress and reactivation of latent herpes simplex virus, and the manifestation of clinical symptoms such as cold sores is well-known. A recent meta-analysis confirmed the presence of a robust connection between psychosocial stress and symptomatic HSV recurrence. Interestingly, psychosocial stress tended to be more strongly associated with oral than genital herpes recurrence.
Recently, stress has been linked to an early onset and delayed resolution of herpetic lesions, reduced viral clearance at the site of infection and draining popliteal lymph nodes (PLNs), and impaired functions of HSV-specific CD8(+) T cells in PLNs. Of note, in mice, these impaired CD8(+) T cell functions are not due to direct effects of stress/corticosterone on the T cells, but the ability of PLN-derived dendritic cells to prime HSV-1-specific CD8(+) T cells is functionally impaired.
In the PNAS article Elizabeth Shirtcliff, Christopher Coe and Seth Pollak studied two different types or groups of adverse childhood experiences. First, a group of postinstitutionalized adolescents who had experienced early caregiving deprivation before adoption into a more normative family context, and second, a sample of adolescents who had experienced substantiated physical abuse and were still residing within their families of origin.
Across 4 school and home days, the authors found that the HSV antibody was higher in both postinstitutionalized and physically-abused adolescents when compared with control participants. These data revealed that a profile of high HSV antibody serves as a sentinel marker of a history of adverse experience during formative development.
The findings are particularly noteworthy because of the clear demonstration that these effects linger even after the resolution of the period of childhood adversity.
The present study is unique in demonstrating these effects with a pediatric population. In the case of the postinstitutionalized adolescents, they had been adopted into more benevolent family conditions by 2.8 years of age on average.
Thus, for many, the period of adversity had been over for nearly a decade before the current assessment. The authors conclude that the susceptibility of the immune system to early caregiving experiences reveals an important aspect of developmental plasticity.
Source: Proc Natl Acad Sci USA 2009, 106:2963
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Updates
Early-life stress is a risk factor in the development of psychiatric disorders. One possibility is that early-life stress may impair adaptive immunity and, therefore, increase vulnerability to initial infection and subsequent reactivation of herpesviruses. Herpesviruses are potential immune-modifying agents that persist as latent infections and can reactivate during periods of stress.
Initially believed to be benign except in cases of immunosuppression, cytomegalovirus (CMV) infection has been found to be associated with a range of negative outcomes, including depression, immunosenescence, neurodegenerative disorders, and reduced lifespan.
In 2019 Bart N. Ford et al. demonstrated that individuals with major depressive disorder who experienced more early-life stress were more likely to test positive for CMV, and this finding was replicated in a confirmation sample despite substantially different inclusion and exclusion criteria.
The study published in JAMA Psychiatry suggests that early CMV infection and subsequent reactivation during stressful periods may be a mechanism through which the consequences of early-life stress affect health.
The study adds vulnerability to CMV (and potentially to other viruses such as herpes simplex virus 1) to the list of consequences of early-life stress. These findings also highlight an avenue of future research that could potentially validate the proposed mechanistic link between herpesviruses and the sequalae of early-life stress and leverage this association to improve clinical outcomes.
A 2020 review includes mechanisms involved in primary infection and the regulation of latency and describes how stress-induced changes increase the susceptibility to primary and recurrent infections.
Figure. The life cycle of HSV-1 in neurons. During the establishment of latency, the virus invades the axonal termini through virion fusion and travels to the nucleus through retrograde transport. Then the virus enters its latency. During latency, the virus maintains itself in the neuron as an episome while silencing most of its genome and transcribing only a series of mRNAs, especially LAT. When stimulated by stress factors, the virus reactivates and starts to massively replicate its lytic gene. The proliferated virus then travels to the axon termini through anterograde transport. The complete assembly of the virion is finished in the process of egression. After the egression, the virus re-infects epithelial cells and causes recurrent lesion (Open Access).
The authors concluded that following by the invasion of HSV-1 into the neurons, the virus travels through microtubules into the nucleus, where most of the HSV-1 genome is silenced due to the specific characteristics of neurons. Epigenetic modification and the direct effect on the latent gene can reduce lytic gene expression, and thus the virus cannot be detected by the immune system. The virus can also deplete T cells to reduce the survey intensity. The Yin–Yang balance between the virus-stimulating and virus-inhibiting factors maintains the latency. Under stress, oxidational damage, increased glucocorticoids and decreased thyroid hormones promote the Yang factors and inhibit the Yin factors, consequently disturbing the Yin–Yang balance, leading to productive viral replication.
A 2021 study by Jeffery B Ostler et al. suggests stressful stimuli can trigger productive infection because GR and specific stress-induced transcription factors activate Infected Cell Protein 4 (ICP4) expression.
Background: Infected Cell Protein 4 (ICP4) is a crucial viral protein produced by Herpes Simplex Virus (HSV) that regulates the expression of other viral genes. It acts as a transcriptional regulator, meaning it controls which genes are turned on or off, and it plays a vital role in the virus’s ability to replicate and establish infection.
The authors of this study hypothesized that stress-induced transcription factors stimulate expression of ICP4, a viral transcriptional regulator required for productive infection.
The 2021 study by Jeffery B Ostler et al. demonstrated GR and specific stress-induced transcription factors cooperatively activate the ICP4 enhancer by directly interacting with KLF4/Sp1 binding sites.
The authors suggest that in addition to directly influencing viral gene expression and replication, the anti-inflammatory and immunosuppressive properties of corticosteroids are likely to promote virus spread following stressful stimuli. Also, KLF4 interferes with antiviral responses by inhibiting ISRE (interferon-stimulated response element) and IRF3 binding to the beta-interferon (IFN-β) promoter. In summary, GR activation may have numerous effects (direct or indirect) on productive infection.
The authors of a 2023 study hypothesized that GR and certain stress-induced transcription factors would stimulate VP16 transcription if the VP16 protein mediates early stages of reactivation. They found that Slug, a Stress-Induced Transcription Factor, stimulates Herpes Simplex Virus 1 replication and transactivates a cis-Regulatory module within the VP16 Promoter. They concluded that this suggest that Slug, by virtue of transactivating VP16 and ICP4 CRM sequences, can trigger reactivation in certain neurons. In conclusion, the study revealed VP16 transcriptional activity is activated by GR and Slug.
A 2025 review by Clinton Jones summarizes GR and stress-induced cellular transcription factors that play an important role during reactivation from latency by activating key viral promoters.
As per the author, successful reactivation from latency is a complex series of HSV-1-neuronal interactions that culminate in the production of infectious virus. During latency, the viral genome is organized as silent chromatin, and LAT plays a crucial role in maintaining latency.
Figure: Schematic of hypothetical steps needed to initiate reactivation from latency. For details, see text. (Open Access).
Consequently, lytic cycle viral protein expression is not readily detected. Following a stressful stimulus that triggers reactivation from latency, the simplest pathway to reactivation entails at least three events: (i) VP16, ICP0, and/or ICP4 promoters are remodeled and subsequently activated, (ii) at least one of these viral regulatory proteins must be expressed, and (iii) the lytic cascade of gene expression occurs culminating in production of infectious virus.
In conclusion, according to the author, the GR and certain stress-induced cellular transcription factors are predicted to drive early stages of reactivation from latency.