Janet E. Leigh

Human papillomavirus infection and disease in HIV-infected individuals

The possibility of increases in both oral and anogenital pathologic conditions due to human papillomavirus (HPV) in patients infected with the human immunodeficiency virus (HIV) is of concern and is the focus of numerous current research studies. HIV-infected women are at higher risk for cervical HPV detection, for infection with high-oncogenic-risk types of HPV, for persistent HPV infection, for cervical cytologic abnormalities, and for cervical intraepithelial neoplasms. HIV-infected men are at increased risk for anal HPV infection, for anal infection with high oncogenic-risk types of HPV, for persistent anal HPV infection, and for anal intraepithelial defects. Recent studies have shown an increased risk of oral warts in HIV-infected individuals despite treatment with highly active antiretroviral therapy (HAART). Oral HPV infection rates have not declined since the initiation of HAART, and evidence suggests that the rates may have actually increased in white HIV-infected males.

Th1/Th2 cytokine expression in saliva of HIV-positive and HIV-negative individuals : A pilot study in HIV-positive individuals with oropharyngeal candidiasis

Current data suggest that T-helper (Th)2-type cytokine responses are often associated with progression to AIDS in HIV-positive individuals. Similarly, Th2-type cytokines are associated with susceptibility to mucosal candidiasis, of which oropharyngeal candidiasis (OPC) is one of the most common opportunistic infections in HIV-positive individuals. Although little information is available on host defense mechanisms at the level of the oral mucosa, recent studies suggest that local cell-mediated immunity (CMI) is equally or more important than that in the periphery for host defense against mucosal Candida albicans infections. This study investigated the potential presence of oral-associated CMI through the expression of Th1/Th2-type cytokines in saliva of immunocompetent and immunocompromised individuals with and without OPC. Results showed a constitutive mixed Th1/Th2 cytokine expression (Th0) in whole saliva of healthy HIV-negative individuals. In contrast, HIV-positive individuals had a dominant Th2-type salivary cytokine profile (interleukin-4 [IL-4], IL-10) (IL-2, interferon-y [IFN-gamma], IL-12) that seemingly resulted from a lack of Th1-type cytokines rather than enhanced Th2-type cytokines. Moreover, pilot analyses of those with OPC showed evidence for a more profound salivary Th2-type profile. Both HIV-positive and HIV-negative patients, irrespective of CD4 counts, had some level of positive in vitro systemic lymphocyte proliferative responses to C albicans antigens. These results suggest that the Th1/Th2 cytokine dichotomy in HIV disease is detectable in situ in oral secretions and may be a useful indicator of oral-associated CMI to better understand resistance/susceptibility of HIV-positive individuals to oral opportunistic infections, including OPC.

Candida-Specific Systemic Cell-Mediated Immune Reactivities in Human Immunodeficiency Virus—Positive Persons with Mucosal Candidiasis

Oropharyngeal candidiasis (OPC), as opposed to vulvovaginal candidiasis (VVC), is a common opportunistic infection in human immunodeficiency virus (HIV)-positive persons that correlates with reduced CD4 T cell counts. Although cell-mediated immunity (CMI) by CD4 Th1-type cells is considered to be the predominant host defense against mucosal candidiasis, the immune factors associated with susceptibility to OPC in HIV-positive persons are not well understood. This study investigated Candida-specific systemic CMI in HIV-positive persons with OPC and/or VVC. Reductions in delayed skin test reactivity to Candida antigen were observed in HIV-positive persons with CD4 cell counts <200 cells/microL, irrespective of the presence of mucosal infection. Likewise, despite the correlate of OPC with reduced CD4 cell counts in HIV-positive persons, differences in Candida-specific peripheral blood mononuclear cell proliferation and Th1/Th2 cytokine production between HIV-positive and HIV-negative persons were not consistent in a manner to suggest that deficiencies in Candida-specific systemic CMI account solely for the susceptibility to OPC.

The impact of highly active antiretroviral therapy and immunodeficiency on human papillomavirus infection of the oral cavity of human immunodeficiency virus-seropositive adults.

Background: Prevalence of human papillomavirus (HPV)–associated oral condylomas has reportedly increased in HIV-infected individuals since the introduction of highly active antiretroviral therapy (HAART). The relationships between HIV therapy regimen, overall health, and subclinical oral HPV have not been examined. Goal: To determine oral HPV genotype prevalence and the impact of HAART and health in the HIV+ population. Study: An L1 consensus-primer polymerase chain reaction and linear array assay were used to examine the prevalence of 27 HPV genotypes in saliva of 98 HIV+ individuals. Risk assessment variables were compared to oral HPV status. Results: Oral HPV was detected in 37% of HIV+ African American individuals. Caucasians were at greater risk of oral HPV infection than African Americans. Markers of advanced HIV disease did not predict HPV status. Therapy status was associated with HPV detection. Conclusions: Treatment of HIV, rather than HIV immunosuppression, appears to play a role in oral HPV infections in HIV+ individuals.

Potential Role for a Carbohydrate Moiety in Anti-Candida Activity of Human Oral Epithelial Cells

ABSTRACT Candida albicans is both a commensal and a pathogen at the oral mucosa. Although an intricate network of host defense mechanisms are expected for protection against oropharyngeal candidiasis, anti-Candida host defense mechanisms at the oral mucosa are poorly understood. Our laboratory recently showed that primary epithelial cells from human oral mucosa, as well as an oral epithelial cell line, inhibit the growth of blastoconidia and/or hyphal phases of several Candida species in vitro with a requirement for cell contact and with no demonstrable role for soluble factors. In the present study, we show that oral epithelial cell-mediated anti-Candida activity is resistant to gamma-irradiation and is not mediated by phagocytosis, nitric oxide, hydrogen peroxide, and superoxide oxidative inhibitory pathways or by nonoxidative components such as soluble defensin and calprotectin peptides. In contrast, epithelial cell-mediated anti-Candida activity was sensitive to heat, paraformaldehyde fixation, and detergents, but these treatments were accompanied by a significant loss in epithelial cell viability. Treatments that removed existing membrane protein or lipid moieties in the presence or absence of protein synthesis inhibitors had no effect on epithelial cell inhibitory activity. In contrast, the epithelial cell-mediated anti-Candida activity was abrogated after treatment of the epithelial cells with periodic acid, suggesting a role for carbohydrates. Adherence of C. albicans to oral epithelial cells was unaffected, indicating that the carbohydrate moiety is exclusively associated with the growth inhibition activity. Subsequent studies that evaluated specific membrane carbohydrate moieties, however, showed no role for sulfated polysaccharides, sialic acid residues, or glucose- and mannose-containing carbohydrates. These results suggest that oral epithelial cell-mediated anti-Candida activity occurs exclusively with viable epithelial cells through contact with C. albicans by an as-yet-undefined carbohydrate moiety.

Immunohistochemical Evaluation of T Cells in Oral Lesions from Human Immunodeficiency Virus-Positive Persons with Oropharyngeal Candidiasis

ABSTRACT Oropharyngeal candidiasis (OPC), caused by Candida albicans, is the most frequent opportunistic fungal infection in human immunodeficiency virus (HIV)-positive persons. Although Th1-type CD4+ T cells are considered important for host defense against mucosal C. albicans infections, there is a paucity of information regarding the presence and/or role of T cells in OPC lesions. In pursuit of this, initial chromophore immunohistochemical studies showed a majority of CD8+ rather than CD4+ cells equally distributed throughout the buccal mucosa of OPC− persons (HIV− or HIV+), irrespective of blood CD4+ cell numbers. In contrast, CD8+ cells in lesions from HIV+ OPC+ persons were in significantly higher numbers and concentrated at the lamina propria-epithelium interface, a considerable distance from the Candida at the outer epithelium. Dual fluorescence and confocal microscopy confirmed that the majority of CD8+, but not CD4+, cells were T cells by the presence or absence, respectively, of CD3 on each cell type. These results suggest that CD8+ T cells may be important for oral host defense against OPC, especially when CD4 cell numbers are reduced, with a potential CD8 cell-specific dysfunction associated with susceptibility to OPC.

Oral Opportunistic Infections in HIV-Positive Individuals: Review and Role of Mucosal Immunity

Oral opportunistic infections in the HIV-positive individual have been documented since the first reports of the epidemic, with many lesions associated with reduced CD4(+) T lymphocyte cell count. The most common oral lesions seen in HIV disease prior to the advent of highly active antiretroviral therapy (HAART) were oropharyngeal candidiasis and oral hairy leukoplakia. However, since the advent of HAART while many oral lesions have decreased significantly the incidence of oral warts has surprisingly increased. Despite the correlation of diminished CD4(+) T lymphocyte count to the occurrence of these lesions, it is rare for the lesions to occur concurrently suggesting that each pathologic lesion type is associated with distinct host immune dysfunctions. To date, the oral opportunistic infection most frequently investigated is oropharyngeal candidiasis, where data suggests that both systemic and local immunity is important for protection against infection. In contrast, recent investigations into the host responses associated with oral hairy leukoplakia and oral warts show little to no evidence of systemic or mucosal immune responsiveness despite the presumed competence of several types of leukocytes other than CD4(+) T cells. Together these data are suggesting that susceptibility to oropharyngeal candidasis in HIV-positive persons is predominantly immune-based, whereas protection or susceptibility to oral hairy leukoplakia and oral warts may be more associated with factors other than mucosal immune function.

Tissue-Associated Cytokine Expression in HIVPositive Persons with Oropharyngeal Candidiasis

Oropharyngeal candidiasis (OPC), caused by Candida albicans, is the most common infection in human immunodeficiency virus (HIV)-positive persons. Although CD4(+) T cells are considered to be important for host defense against C. albicans at the oral mucosa, a recent immunohistochemical evaluation of T cells in OPC lesions of HIV-positive persons with reduced CD4(+) T cells showed high numbers of CD8(+) T cells. The present study investigated tissue-associated expression of cytokine and chemokine mRNA at the site of infection. Results showed some effects of HIV (primarily increased chemokine mRNA levels) but little effect of blood CD4(+) T cells. In contrast, mRNA for several proinflammatory, T helper, and CD8(+) T cell-associated cytokines and chemokines were increased in subjects with OPC versus those without. These results support the presence of CD8(+) T cells in OPC lesions and suggest evidence for a response against OPC, despite reduced levels of CD4(+) T cells.

Characterization of CD8 T Cells and Microenvironment in Oral Lesions of Human Immunodeficiency Virus-Infected Persons with Oropharyngeal Candidiasis

ABSTRACT Oropharyngeal candidiasis (OPC), the most common oral infection in human immunodeficiency virus-positive persons, correlates with reduced blood CD4+ T cells. In those with OPC, CD8+ T cells accumulate at the lamina propria-epithelium interface at a distance from the organism at the outer epithelium. The present study aimed to characterize the tissue-associated CD8+ T cells and tissue microenvironment in both OPC+ and OPC− persons. The results show that the majority of CD8+ T cells possess the αβ T-cell receptor, the thymus-derived αβ CD8 antigen heterodimer, and similar levels of the α4β7, α4β1, and αeβ7 homing receptors. Studies to evaluate the tissue microenvironment showed that in OPC+ persons, the adhesion molecule for T cells to enter mucosa, mucosal addressin cell adhesion molecule, is significantly increased, whereas E-cadherin, which allows T cells to migrate through mucosa, is significantly decreased compared to OPC− persons. These results continue to support a role for CD8+ T cells against OPC under conditions of reduced numbers of CD4+T cells, with susceptibility to infection potentially associated with a dysfunction in mucosal CD8+ T-cell migration by reduced tissue-associated E-cadherin.

Assessment of the association between HIV viral load and CD4 cell count on the occurrence of oropharyngeal candidiasis in HIV-infected patients.

Background: Oropharyngeal candidiasis (OPC) is the most frequently observed oral infection in HIV-infected individuals. Historically, lower CD4 counts have been associated with an increased prevalence of OPC in HIV-infected patients, but HIV viral load has also recently been recognized as a possible predictive factor. Objective: We examined the impact of viral load and blood CD4 cell count on the occurrence of OPC using modern exploratory statistical analyses. Methods: The exploratory and inferential methods of classification and regression trees (CARTs) and logistic regression were used to compare the impact of viral load and CD4 cell counts on OPC status in 161 HIV-infected individuals from an outpatient clinic population in New Orleans. Results: The use of stepwise logistic regression and CART to classify individual OPC status both identified viral load as the most important covariate, followed by CD4 cells counts. Age, sex, and highly active antiretroviral therapy use were also found to be associated with OPC status. Conclusions: These data strongly suggest that low viral load distinguishes those not at risk for OPC with high viral load, which also includes a heterogeneous set of predictors for OPC status, has the highest impact on OPC classification.