Candida-host interactions in HIV disease: implications for oropharyngeal candidiasis

Abstract

Oropharyngeal candidiasis (OPC), caused primarily by Candida albicans, is the most common oral infection in HIV(+) persons. Although Th1-type CD4(+) T cells are the predominant host defense mechanism against OPC, CD8(+) T cells and epithelial cells become important when blood CD4(+) T cells are reduced below a protective threshold during progression to AIDS. In an early cross-sectional study, OPC(+) tissue biopsied from HIV(+) persons had an accumulation of activated memory CD8(+) T cells at the oral epithelial-lamina propria interface, with reduced expression of the adhesion molecule E-cadherin, suggesting a protective role for CD8(+) T cells but a dysfunction in the mucosal migration of the cells. In a subsequent 1-year longitudinal study, OPC(-) patients with high oral Candida colonization (indicative of a preclinical OPC condition), had higher numbers of CD8(+) T cells distributed throughout the tissue, with normal E-cadherin expression. In OPC(+) patients, where lack of CD8(+) T cell migration was associated with reduced E-cadherin, subsequent evaluations following successful treatment of infection revealed normal E-cadherin expression and cellular distribution. Regarding epithelial cell responses, intact oral epithelial cells exhibit fungistatic activity via an acid-labile protein moiety. A proteomic analysis revealed that annexin A1 is a strong candidate for the effector moiety. The current hypothesis is that under reduced CD4(+) T cells, HIV(+) persons protected from OPC have CD8(+) T cells that migrate to the site of a preclinical infection under normal expression of E-cadherin, whereas those with OPC have a transient reduction in E-cadherin that prohibits CD8(+) T cells from migrating for effector function. Oral epithelial cells concomitantly function through annexin A1 to keep Candida in a commensal state but can easily be overwhelmed, thereby contributing to susceptibility to OPC.

Fig.

Proposed immune function of the oral mucosa in HIV⁺ individuals with and without oropharyngeal candidiasis (OPC) and < 200 CD4 cells/µL. Left frame depicts the protective mechanisms associated with the HIV⁺ OPC⁻ individual colonized with Candida albicans when the primary defense of CD4⁺ T cells is below the protective threshold (200 cells/µL). The secondary defense consists of CD8⁺ T cells migrating to the outer epithelium under normal expression of E-cadherin and functional oral epithelial cell anti-Candida activity that together keep Candida “in check” and prevent symptomatic infection. Th1 cytokines in saliva may also act in protection against infection, along with cytokines in tissue. Right frame depicts the condition of OPC. In this scenario, when CD4⁺ T cells are below the protective threshold, CD8⁺ T cells are inhibited from migrating to Candida for effector function because of a transient reduction in E-cadherin, and the epithelial cells have reduced capacity to inhibit Candida, resulting in Candida overgrowth and symptomatic infection. Reduced Th1 cytokines in saliva may also contribute to the susceptibility.