Although HIV transmission through the oral mucosa is a relatively rare event [77
], it can occur through genital-oral or breastfeeding routes. Numerous studies have described the transmission of the virus from mothers to children during lactation [78
] demonstrating that, although uncommon compared with vaginal and rectal sexual transmission, HIV infection via the oral cavity is clearly possible. The presence of virions in saliva, salivary glands, and buccal epithelial cells is well documented [79
]; however, it is still controversial whether saliva is a real route of HIV transmission. On the other hand, how the innate immune and related protective properties of oral mucosal epithelium might control HIV infection during clinical exposure to infectious virus is becoming an area of intense interest. This stems from multiple studies and epidemiological reports suggesting that the oral mucosa is not as permissive for efficient HIV replication as other mucosal epithelia (e.g., vagina/cervix and anal/rectal) and, therefore, may differ in susceptibility when compared to these mucosal sites. Discovering factors that explain the differential susceptibility and resistance to HIV infection in mucosal sites will allow for the identification and development of novel protective strategies.
Potential Role of Salivary and Epithelial Innate Immune Effector Molecules during Infection with HIV
The relative infrequency of oral HIV infection can be posited to involve: (i) a thick multilayered mucosal surface as the first line of defense against microbial invasion, (ii) low salivary HIV titers, and (iii) endogenous antiviral factors present in oral secretions. Many endogenous inhibitors of HIV in saliva have been proposed (e.g., amylase, lactoferrin, proline-rich peptides, salivary mucins, thrombospondin and secretory leukocyte protease inhibitor or SLPI)[80
]. Remarkably, these agents are also found in seminal fluid and vaginal secretions, routinely harvested from sites that are more susceptible to HIV infection [83
]. Furthermore, fresh human saliva cannot inactivate HIV rapidly enough to prevent entry of infectious virus into oral keratinocytes [85
]. It is clear, therefore, that more information is needed to understand whether salivary innate immune factors contribute efficiently to the resistance against acquisition of HIV.
Mucosal epithelial cells also express antimicrobial peptides with antiretroviral activity. In addition to SLPI, oral epithelial cell-derived human β defensins (hBDs)[86
] inhibit HIV infection of immunocompetent cells in vitro
]. When compared with adult oral mucosae, the lack of hBD and SLPI expression in fetal oral mucosae appears to render underlying immunocompetent cells more susceptible to HIV infection [89
]. While transcytosis of the virions is not appreciably different in adult and fetal mucosal cells, the ease with which HIV infects the underlying lymphocytes in the fetal mucosal model, and the loss of protection by use of specific antibodies to hBDs and SLPI in the adult oral mucosae, strongly suggest that these peptides protect against HIV infection [89
]. Interestingly, a notable difference between oral epithelia and most other epithelia is the constitutive expression of hBDs. These defensins are expressed only in the presence of infection or inflammation in most tissues, including skin, trachea and gut epithelium [90
]. However, both hBD-2 and -3 are expressed in normal uninflamed gingival tissue [92
], perhaps due to chronic exposure to specific oral commensal bacteria that promote hBD expression [93
]. What is less clear is whether the target cells for antiviral activity are the hBD-producing oral epithelial cells or the proximal immunocompetent cells.
Despite the myriad of studies on HIV transmission during the last thirty years, definitive information about the fate of the HIV virion in the mucosal epithelium is absent. Greater understanding of vulnerable versus less susceptible mucosal sites may help identify strategies to prevent HIV transmission. For example, it would be interesting to compare anatomic structure of different mucosal epithelia (i.e., vaginal, cervical, colorectal, intestinal, and oral) with function during HIV exposure, resting and, active HIV infection in naïve patients or treated with antiretroviral drugs. Deciphering the mechanisms underlying HIV infection through the human mucosal sites will hopefully aid in the development of novel and less invasive prophylactic strategies to prevent HIV transmission.