Plausibility of HIV-1 Infection of Oral Mucosal Epithelial Cells

Abstract

The AIDS pandemic continues. Little is understood about how HIV gains access to permissive cells across mucosal surfaces, yet such knowledge is crucial to the development of successful topical anti-HIV-1 agents and mucosal vaccines. HIV-1 rapidly internalizes and integrates into the mucosal keratinocyte genome, and integrated copies of HIV-1 persist upon cell passage. The virus does not appear to replicate, and the infection may become latent. Interactions between HIV-1 and oral keratinocytes have been modeled in the context of key environmental factors, including putative copathogens and saliva. In keratinocytes, HIV-1 internalizes within minutes; in saliva, an infectious fraction escapes inactivation and is harbored and transferable to permissive target cells for up to 48 hours. When incubated with the common oral pathogen Porphyromonas gingivalis, CCR5- oral keratinocytes signal through protease-activated receptors and Toll-like receptors to induce expression of CCR5, which increases selective uptake of infectious R5-tropic HIV-1 into oral keratinocytes and transfer to permissive cells. Hence, oral keratinocytes-like squamous keratinocytes of other tissues-may be targets for low-level HIV-1 internalization and subsequent dissemination by transfer to permissive cells.

Fig. 1.

Nonproductive infection of oral keratinocytes by HIV-1. X4- or R5-tropic HIV-1 binds and internalizes into oral keratinocytes in a manner independent of the chemokine coreceptor specificity (CXCR4 or CCR5). A noncanonical HIV-1 receptor likely exists—perhaps, a surrogate for CD4. X4- and R5-tropic HIV-1 internalizes in the keratinocyte and uncoats, and viral RNA is reverse transcribed and integrates into the keratinocyte genome. Integration is stable, but new HIV-1 transcripts are not detected.

Fig. 2.

R5-HIV and Porphyromonas gingivalis coinfection of oral epithelial cells: (A) P. gingivalis gingipains signal oral keratinocytes through PAR-1 and PAR-2, and LPS signals through TLR2 and TLR4. (B) Signaling of the oral epithelial cell leads to upregulation and expression of CCR5 on cell surface. (C) P. gingivalis–upregulated CCR5 promotes selective internalization of R5 HIV-1 and intracellular harboring. (D) Harbored infectious virions in oral keratinocytes are trans-infected to permissive cells. R5 HIV-1 is transferred and captured by CD4+ permissive cells, where virus replicates and dissemination can occur.