Fate of HIV-1 in Oral Epithelial Cells

At mucosal surfaces, HIV-1 infection occurs in the polymicrobial environment of resident commensal and pathogenic flora. To learn the fate of HIV-1 in squamous oral mucosal epithelium, we have developed an in vitro infection model that incorporates key environmental factors: saliva and co-pathogens. In immortalized oral keratinocytes, infection with X4- and R5-tropic HIV-1 aborts. During infection, integration of HIV-1 occurs at a low level and persists upon subculture, but new viral transcripts are undetectable. Keratinocytes, however, can harbour infectious X4- and R5-tropic HIV-1, which can trans infect permissive cells. When inoculated in inactivating doses of human saliva, HIV-1 is rapidly sequestered in keratinocytes and remains sufficiently infectious to trans infect permissive cells. We modelled the effect of a key indigenous and ubiquitous pathogen, P. gingivalis, on the fate of HIV-1 in oral keratinocytes. P. gingivalis up-regulates expression of the HIV-1 co-receptor CCR5 on oral keratinocytes and increases the uptake, internalization and transfer of infectious R5-tropic HIV-1 to permissive cells. Generally not expressed by oral epithelium except during inflammation, CCR5 is regulated primarily through a protease-activated receptor-dependent pathway with independent signalling through Toll-like receptors 2 and 4. P. gingivalis-mediated up-regulation of CCR5 could contribute to the greater prevalence of R5-tropic primary infections. Furthermore, we now show that infection with P. gingivalis largely prevents the HIV-1-induced suppression of the interferon-related gene response in oral keratinocytes. Hence, P. gingivalis shows profound effects on the fate of a major pathogenic virus in human mucosal keratinocytes. In the presence of environmental factors that modify infection, some of which have correlates on other epithelia, mucosal epithelial cells could represent a cryptic reservoir of infectious HIV-1.

Supported by NIH/NIDCR R01DE015503