Maintenance of oral health is dependent on preserving the homeostatic balance between host and the distinct microbial communities that colonize the various anatomical microenvironments in the oral cavity. HIV infected patients often display increased susceptibility to opportunistic oral infections that are presumably linked, in part, to disruption of host-microbe homeostasis (dysbiosis). In the current study, we utilize HOMIM-based analyses to characterize and compare the bacterial composition of the lingual microbiome in a relatively small, but well-defined cohort of untreated chronically HIV infected patients (n
6), HIV patients on ART (n
6), and uninfected controls (n
9). Due to the small sample sizes, it is important to caution that our findings represent a preliminary indication of the impact of HIV infection on the community structure of the oral microbiome. Indeed, the microbiome of even a single individual can be difficult to define, consisting of entrenched endogenous species and transient species whose prevalence can vary depending on time of sampling, diet, oral hygiene, and numerous other parameters [19
]. Extensive cross sectional and longitudinal sampling of patients with and without oral manifestations will ultimately be necessary to fully characterize the role of the microbiota in HIV associated oral pathogenesis. The current study represents an important first step towards that goal. Our findings indicate that chronic HIV infection may lead to substantial disruptions in the community structure of the lingual microbiota, even in the absence of clinical oral manifestations.
Several potential mechanisms that have been revealed in previous studies may contribute to the development of host-microbe dysbiosis in the oral mucosa during immunodeficiency virus infection. Recently, analysis of SIV infected rhesus macaques demonstrated that, similar to the gut mucosa, depletion of CD4+ T cells from the oral mucosa is rapid and dramatic [10
]. This finding underscores the likelihood that immune dysfunction resulting from the loss of CD4+ T cell activity in the oral cavity could contribute to the development of oral manifestations during SIV/HIV infection. Recent studies suggest that Notch-1 signaling mediates epithelial barrier function in the gut through interaction with CD4+ T cells [25
]. Although interaction of Notch-1 with CD4+ T cells has not been studied in the oral mucosa, Notch-1 signaling is known to mediate oral epithelial cell differentiation [26
]. Thus, it is possible that CD4+ T cell depletion from the oral mucosa of HIV infected subjects may also lead to the impairment of epithelial growth and, by extension, host-microbe dysbiosis.
In addition, depletion of the Th17 subset of CD4+ T cells has been shown in the gut mucosa impair response to microbial infections [8
], in part by dampening expression of epithelial antimicrobial peptides [28
]. HIV patients display decreased expression of histatin-5, a potent antimycotic known to inhibit the growth of Candida albicans
]. Moreover, in vitro
studies suggest that X4-tropic HIV can inhibit expression of human beta defensin-2 (hBD-2) and other innate immune factors in differentiated oral epithelium [30
]. Because hBD-2 functions as a chemoattractant for dendritic cells in addition to its antimicrobial activity [31
], the loss of hBD-2 during HIV infection could potentiate the colonization of pathogenic species through multiple mechanisms. Thus, it is conceivable that, similar to the gut mucosa, Th17 cells may be depleted from the oral mucosa in SIV/HIV infection, thereby providing a potential mechanism for increased susceptibility to dysbiosis and infection from C. albicans
and other non-commensal pathogens.
Interestingly, one of the largest and most consistent alterations we detected in the oral microbiome of untreated HIV patients was a shift in the representation of Veillonella
species. Although the relative percentage of Veillonella
dropped from ~19% of the total lingual bacterial population in healthy controls to just over 10% in untreated HIV infected subjects, that same group displayed a uniform increase in the growth of V. parvula
. While V. parvula
is a commensal gram negative anaerobic coccus in healthy individuals [32
], it is also the only known Veillonella
species associated with oral disease. V. parvula
has been implicated in severe early childhood caries [33
], primary endodontic infections [34
], and other periodontal diseases [35
]. Recent studies indicate that V. parvula
lipopolysaccharide (LPS) stimulates pro-inflammatory cytokine production and p38 MAPK activation through TLR-4 dependent mechanisms [36
]. Thus, it is possible that increased V. parvula
colonization (as well as other opportunistic pathogens) could establish an inflammatory environment in the oral cavity, that in turn, contributes to the chronic inflammation and immune activation that characterizes HIV disease progression. Future studies are warranted to determine whether increased colonization of putative periodontal pathogens on the tongue epithelium reflects similar increased growth in gingival and subgingival tissues, and perhaps a systemic distribution to more distal mucosal compartments.