Are There Clues to Oral Kaposi Sarcoma–Associated Herpesvirus Shedding and Kaposi Sarcoma Oncogenesis in the Oral Microbiome?

(See the Major Article by Dai et al., on pages 1331–41.)

In this issue of The Journal of Infectious Diseases, Dai et al present data from a series of experiments that provide insights into the pathogenesis of oral Kaposi sarcoma (KS), a virus-induced angioproliferative neoplastic disease and AIDS-defining condition [1]. KS-associated herpesvirus (KSHV), also known as human herpesvirus 8, was identified as the causative agent for KS in 1994 [2]. This discovery by Chang et al ushered in a new era of basic and clinical research that revolutionized the understanding of several AIDS-related neoplastic diseases. KSHV was rapidly shown to be the necessary, although alone insufficient, causative agent for KS, primary effusion lymphoma, and a form of multicentric Castleman disease [3, 4]. Additionally, owing in part to the increased understanding of this gammaherpesvirus’s genes expression under various conditions, a KSHV-related cytokine syndrome was described [5, 6].

The quest for understanding KSHV-related neoplasia generated research aimed at identification of cofactors that could influence which of these KSHV-related diseases might become manifest. Evident early on was that immunodepletion due to untreated HIV infection clearly establishes the highest risk for KSHV-related disease. With effective combination antiretroviral therapy, the risk of AIDS-related cancers decreased. KS can sometimes respond to initiation of human immunodeficiency virus (HIV) therapy without any additional KS-directed treatment [7]. Nonetheless, >20 years into the use of effective antiretroviral therapy, KS persists as an important HIV-associated cancer, albeit in an evolving clinical context [8]. Among other potential cofactors are volcanic rock; interactions with anthropods, such as sand flies; “oncoweeds,” which are natural products with latency reversal activity [9]; malaria; and hypoxia, for KS involving the extremities [10–12].

KSHV may spread through saliva. Epidemiological and molecular evidence supports saliva as a conveyor of KSHV from mother to infant; KSHV also appears to be spread during male-to-male sexual activity when saliva is used as a lubricant [13, 14]. Interestingly, it is not clear that the KSHV viral burden in the saliva correlates with development of oral KS [15, 16]. Furthermore, unlike with systemic KS, the effect of CD4⁺ T-cell status alone does not account for oral KSHV shedding [17]. These findings suggest that other factors, perhaps in the microenvironment, affect KS tumorigenesis. For oral KS and KSHV shedding, the oral microbiome is an intriguing cofactor [18].

Dai et al, building on earlier work showing that pathogen-associated molecular patterns (PAMPs) promoted KSHV entry into oral cells and subsequent establishment of latency, have now demonstrated that Staphylococcus aureus and its PAMPs can effectively induce KSHV lytic reactivation from infected oral cells [1, 19]. Toll-like receptor (TLR) reactive oxygen species (ROS) induced by these PAMPs downregulate the cyclin D1-Dicer-viral microRNA axis, thus promoting infectious propagation by balancing lytic cell killing and cell viability. In this way, KSHV can undergo lytic replication and infection of new cells without mass cell killing, setting the stage for development and propagation of KS tumors in the mouth. These authors were able to show in controlled experiments that KSHV genes such as those encoding the viral G–coupled protein receptor and the lytic transactivator RTA relevant to KS pathogenesis were activated in S. aureus–conditioned medium and by S. aureus–derived lipoteichoic acid. Induction of infectious virion release was also shown in these experiments. The effect was not seen with other gram-positive bacteria tested, suggesting that S. aureus may be playing an important role as a clinical cofactor. Pretreatment with the antioxidant N-acetylcysteine effectively blocked viral lytic gene expression, showing that TLR2-mediated ROS production and signaling is required for induction of KSHV lytic reactivation by S. aureus–conditioned medium. The investigators also evaluated saliva from individuals with and those without HIV infection, as well as individuals with and those without KSHV. The clinical relevance of these experiments is suggested by the finding that, among individuals with HIV infection, those with KSHV infection had higher levels of total salivary lipoteichoic acid than those without evidence of KSHV infection. Although S. aureus–related lipoteichoic acid cannot be directly measured, the inability to find KHSV induction by other bacterial PAMPS implicates S. aureus as the relevant PMAP source. Thus the salivary findings support the concept that periodontal S. aureus–derived PAMPs play a role in oral KSHV pathogenesis.

The role of viral lytic expression, cell killing, and KS propagation is not fully understood. Rapid and complete virus-induced cell death could serve to limit infection and tumor formation. Dai et al showed a possible mechanism to limit cell death that could promote further cellular spread of KSHV. Expression of cyclin D1 is suppressed in S. aureus–conditioned medium. KSHV-infected cells demonstrated increased S. aureus internalization, and this appeared to be instrumental in preserving cell viability and infectious spread of KSHV in the mouth.

These findings provide potential new insights into oral KSHV pathogenesis. The investigators propose that it is in this way that, in the immunocompromised state, periodontal disease, for which S. aureus is a commonly involved pathogen, promotes development of overt KS. Perhaps this is a missing link to understanding why KS so often involves the oral cavity but appears unrelated to the KSHV viral burden.

Perhaps more importantly, could these observations provide clues to the evident role of KSHV transmission in the saliva? The article does not fully answer these questions but does provide insights into mechanisms in KSHV infection and cellular spread. Oral KS is certainly more complex than the interaction with PAMPs shown here and would require a better understanding of additional factors that lead to spindle cell tumors. The KSHV genome produces viral homologues of a variety of human inflammatory cytokines, genes, and oncogenes that promote KS [20, 21]. Yet, the data the investigators provide from limited patient specimens seem to tell a story that provides a sound scientific hypothesis that S. aureus plays a cofactor role in initiating development of oral KS. What makes this idea so provocative is the possibility that effective public health efforts aimed at the altering the oral microbiome could be created to reduce the burden of KS and KSHV transmission. Could KSHV transmission be inhibited and the oral KS incidence be reduced by efforts to enhance oral hygiene and reduce morbidity associated with periodontal disease? Reducing the prevalence of periodontal disease, a condition that has been associated with myriad health effects, including Alzheimer disease, cardiovascular problems, gastrointestinal cancer, and adverse pregnancy outcomes, is of itself a worthy public health goal [22]. Perhaps KS, as well as infection-related cancer, can be added to the list of conditions that might be favorably affected by efforts to improve oral health.

Notes

Potential conflicts of interest. T. S. U. reports receiving support from Celgene, Merck, Roche outside of the submitted work and holds a patent for pomalidomide, to treat KSHV-associated lymphoma. R. F. L. certifies no potential conflicts. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.