HIV Infection and Compromised Mucosal Immunity: Oral Manifestations and Systemic Inflammation

Abstract

Mucosal surfaces account for the vast majority of HIV transmission. In adults, HIV transmission occurs mainly by vaginal and rectal routes but rarely via oral route. By contrast, pediatric HIV infections could be as the result of oral route by breastfeeding. As such mucosal surfaces play a crucial role in HIV acquisition, and spread of the virus depends on its ability to cross a mucosal barrier. HIV selectively infects, depletes, and/or dysregulates multiple arms of the human immune system particularly at the mucosal sites and causes substantial irreversible damage to the mucosal barriers. This leads to microbial products translocation and subsequently hyper-immune activation. Although introduction of antiretroviral therapy (ART) has led to significant reduction in morbidity and mortality of HIV-infected patients, viral replication persists. As a result, antigen presence and immune activation are linked to "inflammaging" that attributes to a pro-inflammatory environment and the accelerated aging process in HIV patients. HIV infection is also associated with the prevalence of oral mucosal infections and dysregulation of oral microbiota, both of which may compromise the oral mucosal immunity of HIV-infected individuals. In addition, impaired oral immunity in HIV infection may predispose the patients to periodontal diseases that are associated with systemic inflammation and increased risk of cardiovascular diseases. The purpose of this review is to examine existing evidence regarding the role of innate and cellular components of the oral cavity in HIV infection and how HIV infection may drive systemic hyper-immune activation in these patients. We will also discuss current knowledge on HIV oral transmission, HIV immunosenescence in relation to the oral mucosal alterations during the course of HIV infection and periodontal disease. Finally, we discuss oral manifestations associated with HIV infection and how HIV infection and ART influence the oral microbiome. Therefore, unraveling how HIV compromises the integrity of the oral mucosal tissues and innate immune components of the oral cavity and its association with induction of chronic inflammation are critical for the development of effective preventive interventions and therapeutic strategies.

Keywords: HIV; immune activation; immunosenescence; mucosal immunity; oral mucosa; periodontal disease.

Figure 1

Mechanisms by which salivary inhibitors may disrupt HIV-1 infection. (1) Virus-specific antibodies (predominantly IgA) neutralize free-floating virus. (2) Thrombospondin, acidic proline-rich proteins (PRPs), and polyanionic proteins block cell binding by interfering with gp120 on the virus. (3) Secretory leukocyte protease inhibitor (SLPI) and β-defensin disrupt the virion from binding to T cell or macrophage. (4) β-defensin also internalizes and downregulates CXCR4 coreceptor to deny cellular entry. (5) Mucins and salivary agglutinins bind to gp120 and remove it from the virion making it defective. (6) The hypotonicity of the saliva lyses infected cells as well as physically blocking the CD4 coreceptor. (7) Cystatins interfere with proteolytic processes by inhibiting viral cysteine proteases (, , , –110).

Figure 2

Regulation of Candida albicans growth in a healthy oral cavity versus HIV-infected oral cavity. In a state of health, T helper 17 (Th17) cells secrete IL-17 to induce the parotid gland to secrete β-defensin 2/3 in the saliva. β-defensins inhibit C. albicans growth. IL-17 also binds to IL-17R on oral epithelial cells to express CXC chemokines to recruit neutrophils to the oral cavity to also combat C. albicans. Oral epithelial cells, neutrophils, and resident macrophages secrete antifungal cytokines and nitrogen species such as nitric oxide (NO) to kill C. albicans. During the HIV infection, HIV infects and eliminates Th17 cells. Thus, reduction in IL-17 secretion prevents induction of β-defensins, downregulates CXC chemokines expression, and decreases production of other antifungal cytokines. As a result, transition of C. albicans to pathogenic hyphae form occurs.

Figure 3

Proposed mechanisms of oral immune regulation in health versus immune-pathology associated with oral disease and impact of that on HIV acquisition. In a healthy state, the epithelial cells are able to maintain microbial colonization and there is a suppressed immune environment. Gingivitis disrupts normal immune homeostasis leading to a switch from a suppressed environment to a pro-inflammatory state. Activated immune cells incite pro-inflammatory responses and disturb epithelial tight junctions allowing entry of bacterial products with activation of cells that circulate in the peripheral blood. Once gingivitis has progressed to periodontitis, there is complete breakdown of the epithelium allowing microbial products to enter the blood stream and travel systemically. Disruption of epithelial tight junctions and immune activation also facilitates HIV acquisition in the oral cavity.