After infection, virus–immune system interactions can develop in different ways. In some cases, the organism completely eliminates the virus. In others, the virus persists, as in Epstein–Barr virus (EBV) infection. A third scenario involves gradual deterioration, such as progression from HIV infection to AIDS.
EBV infection is associated with an increased risk of Hodgkin lymphoma, multiple sclerosis, and certain autoimmune diseases, although these relationships remain insufficiently understood.
Modern DNA sequencing methods have made it possible to characterize the blood virome — the collection of viruses persistently present in the human body. The virome includes herpesviruses, which can remain latent for long periods, and anelloviruses, which are considered neutral or potentially beneficial. Viral load — the amount of virus in the body — changes over time and reflects immune system status. Its increase often indicates weakened immune control and may be associated with disease development, either due to reactivation of existing viruses or increased susceptibility to new infections.
Researchers from Harvard Medical School analyzed DNA sequencing data from more than 900,000 individuals and assessed levels of 31 common DNA viruses in blood and saliva. This allowed them to identify factors influencing the composition of the human virome.
The analysis showed that viral load is influenced by genetics, age, sex, time of day, season, and smoking, with effects differing in magnitude depending on the virus.
Viral DNA in Blood and Saliva
Viral load depends on tissue type and the specific virus. Saliva better reflects active viral replication processes.
In blood, viral DNA is rarely detected due to the low proportion of infected cells in latent infections. Exceptions include active infections (e.g., parvovirus B19) and viruses integrated into the human genome (e.g., human herpesvirus 6 — HHV-6).
In saliva, viral DNA is detected much more frequently and in higher quantities. Herpesviruses are either absent or present in high copy numbers, indicating episodes of active replication rather than constant latency. Different viruses behave differently: for example, HHV-7 is detected almost continuously, whereas EBV appears irregularly.
In contrast, anelloviruses are rarely detected in both blood and saliva, reflecting their distinct replication cycle.
How Viral Load Changes – Effects of Age, Sex, and Time
Analysis of blood samples. In older individuals, EBV and anelloviruses are more prevalent, whereas in younger individuals HHV-6B and HHV-7 are more common and present at higher levels, decreasing over time.
Analysis of saliva samples. The prevalence of most viruses increases rapidly in early life, after which patterns diverge: EBV DNA accumulates with age, while HHV-6B DNA decreases – possibly indicating stronger adaptive immune control.
For seven viruses, viral load is consistently higher in men than in women. This effect appears already during adolescence.
Circadian and seasonal fluctuations are also observed:
- for EBV and HHV-7, prevalence increases approximately 1.2–1.3-fold between 09:00 and 20:00;
- EBV prevalence is about 1.3 times higher in winter than in summer, whereas HHV-7 shows more moderate seasonal variation.
Different viruses also show varying prevalence across populations of different ancestry.
Genetics and Control of Viral Load
The strongest effects were associated with genes in the major histocompatibility complex (MHC) region. Depending on genetic variants, viral load varied by:
- 56% for EBV;
- 32% for HHV-7;
- 14–30% for anelloviruses.
According to blood sample analysis, the allele DRB104:04* — a variant of the gene encoding human leukocyte antigen (HLA) — is associated with nearly a twofold increase in EBV prevalence.
DRB1 acts as a coreceptor through which EBV enters cells. The DRB104:04* variant may alter the receptor structure, enhancing its binding to the viral protein gp42, facilitating viral entry and increasing infection susceptibility.
In addition to MHC, viral load is influenced by genes involved in antigen presentation (ERAP1/2), antiviral defense, apoptosis, and survival of infected cells.
Viral strain also influences viral load. Two EBV strains – types 1 and 2 – differ in key genes associated with latency. Type 2 EBV is more common in individuals of African ancestry and is associated with a stronger antibody response. The allele HLA-B08:01* reduces susceptibility to EBV type 1 but increases susceptibility to type 2.
High EBV Viral Load as a Risk Factor for Hodgkin Lymphoma
Elevated viral load is characteristic of conditions associated with impaired immune function and inflammation – including AIDS, anemia, diabetes, and renal failure. Immunosuppression, such as after organ transplantation, is associated with increased anellovirus and EBV loads.
Smoking shows opposite effects: it significantly increases EBV load (nearly twofold in heavy smokers compared to non-smokers) but decreases HHV-7 load.
Post-infection EBV viral load significantly influences the development of Hodgkin lymphoma. Higher EBV load in blood likely indicates that more B cells harbor the virus in a latent state. This increases the number of infected cells and the probability of malignant transformation, ultimately contributing to Hodgkin lymphoma development.
Conclusion
Viral load is determined by multiple genetic factors, primarily within the MHC region, with virus-specific effects. Alleles that protect against one virus may increase susceptibility to another.
Elevated EBV load is a risk factor for Hodgkin lymphoma. Antiviral agents, such as acyclic nucleoside analogs that inhibit herpesvirus replication and reduce EBV load in blood, may be beneficial for preventing Hodgkin lymphoma.
Reference
The DNA virome varies with human genes and environments
