The Oral Virome: A missing Piece to the Periodontal Puzzle?
Updated: Jun 23
Over the past several years many studies have focused on the oral microbiome and the relationship between either homeostasis or dysbiosis and health. Scientists have discovered a clear link between the microbiome and health. The oral microbiome is an important part of oral health and disease, but what part, if any does the oral virome play?
I am sure there are plenty of people that have never heard of a virome, therefore I would like to start by defining virome. The virome is one part of the microbiome, it is the collection of viruses found associated with an ecosystem, organism, or a species. There are some important aspects of viruses and the virome that need to be understood. The first important thing to understand about viruses that make up the human virome is that not all viruses are pathogenic. The other important factor is that viruses are the fastest mutating genetic element on earth. 
The study of the virome and its relationship to periodontal disease is in the incredibly early stages. Viruses are much more difficult and expensive to study when compared to bacteria, therefore only recently have scientists had the technology to really dive into their role in periodontal disease and overall health. Studies thus far have indicated a possible relationship between several herpesviruses and periodontal disease. These include herpes simplex 1(HSV-1), Epstein Barr virus (EBV), and human cytomegalovirus (HCMV). 
Etiology and Pathogenesis
Herpesviruses are the most common viruses in humans, an estimated 80-90% of the global population has been infected with one or more herpesviruses. Herpesviruses are enveloped double-stranded DNA viruses that establish lifelong infection in their host. Herpesviruses transition between two states during their lifecycle; lytic and latent replication. Herpesviruses can successfully evade and combat the innate and adaptive immune response.[3,4,5]
Upon infection, the immune response is the same as any other viral infection, an inflammatory reaction occurs through secretion of certain peptides, cytokines, and chemokines. Simply put, herpesviruses overcome the innate immune response by producing anti-cytokine mechanisms as well as inhibiting apoptosis. It evades the adaptive response by moving into a latent phase and limiting antigen expression. Each virus from the herpesvirus family has developed its own unique way to avoid alerting T-cells, allowing the virus to remain in cells for life with occasional proliferation. [6,7]
Periodontal disease and herpesvirus
There have been multiple studies on the relationship between herpesvirus and periodontal disease. Though it can prove to be challenging, there is a clear increased prevalence of subgingival herpesvirus in patients with chronic and aggressive periodontal disease when compared to healthy patients. 
This knowledge has sparked a hypothesis that “a bacterial etiology alone cannot explain the clinicopathologic features presented in the disease”. Some evidence supports this hypothesis with results showing the presence of certain viruses promotes the progression of periodontal disease. However, there are some studies that have found only a weak association or even the opposite results. These inconsistent results prompted a meta-analysis to determine if there was indeed an association between periodontal disease and herpesvirus.
The meta-analysis determined EBV and HCMV had a significant association with an increased risk of periodontal disease. However, there is insufficient evidence to support an association between HSV-1 and HHV-7 (Human Herpesvirus-7), more studies are needed to clarify if there is a true association with these two viruses and periodontal disease. No other members of the herpesvirus family were included in the meta-analysis. 
In a more recently published meta-analysis, the questions concerning the association between HSV-1 and periodontal disease were answered. In this study, the results showed a significant association between HSV-1 and HCMV and the risk of aggressive periodontitis. The evidence was inconclusive as it applies to EBV, and insufficient evidence to support an association with HHV-7 and HSV-2. The exact pathogenic mechanism remains unclear at this time, nevertheless, I am hopeful that further studies will define the mechanism of action giving dental professionals a better understanding and guidance on treating a patient with this co-infection. 
Though more studies and better understanding is warranted, there appears to be an additional concern to address when treating periodontally involved patients. With the lack of guidance, one can only wait for further recommendations, the possibility of adding an anti-viral as an adjunctive treatment during periodontal therapy for patients with a known infection may be an option in the future for better disease management. Periodontal disease has historically been a complex disease, with better science and more research we are learning new ways to address this chronic inflammatory disease that has plagued humans for centuries.
1. Virgin HW. The virome in mammalian physiology and disease. Cell. 2014;157(1):142‐150. doi:10.1016/j.cell.2014.02.032. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3977141/
2. Gao, L., Kang, M., Zhang, M.J. et al. Polymicrobial periodontal disease triggers a wide radius of effect and unique virome. npj Biofilms Microbiomes 6, 10 (2020). https://doi.org/10.1038/s41522-020-0120-7. Retrieved from https://www.nature.com/articles/s41522-020-0120-7#citeas
3. Zhu C, Li F, Wong MC, Feng XP, Lu HX, Xu W. Association between Herpesviruses and Chronic Periodontitis: A Meta-Analysis Based on Case-Control Studies. PLoS One. 2015;10(12):e0144319. Published 2015 Dec 14. doi:10.1371/journal.pone.0144319. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4677929/
4. Hancock MH, Skalsky RL. Roles of Non-coding RNAs During Herpesvirus Infection. Curr Top Microbiol Immunol. 2018;419:243‐280. doi:10.1007/82_2017_31. Retrieved from https://pubmed.ncbi.nlm.nih.gov/28674945/?from_term=+herpesvirus&from_pos=3
5. Stack G, Stacey MA, Humphreys IR. Herpesvirus exploitation of host immune inhibitory pathways. Viruses. 2012;4(8):1182‐1201. doi:10.3390/v4081182. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3446756/
6. Melchjorsen J, Matikainen S, Paludan SR. Activation and evasion of innate antiviral immunity by herpes simplex virus. Viruses. 2009;1(3):737‐759. doi:10.3390/v1030737. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3185509/
7. Feng P, Moses A, Früh K. Evasion of adaptive and innate immune response mechanisms by γ-herpesviruses. Curr Opin Virol. 2013;3(3):285‐295. doi:10.1016/j.coviro.2013.05.011. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4397892/
8. Slots J. Periodontal herpesviruses: prevalence, pathogenicity, systemic risk. Periodontol 2000. 2015;69(1):28‐45. doi:10.1111/prd.12085. Retrieved from https://pubmed.ncbi.nlm.nih.gov/26252400/
9. Li F, Zhu C, Deng FY, Wong MCM, Lu HX, Feng XP. Herpesviruses in etiopathogenesis of aggressive periodontitis: A meta-analysis based on case-control studies. PLoS One. 2017;12(10):e0186373. Published 2017 Oct 16. doi:10.1371/journal.pone.0186373. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5643052/