Relationship of Cell Bearing EBER and p24 Antigens in Biopsy-proven Lymphocytic Interstitial Pneumonia in HIV-1 Subtype E Infected Children

Abstract

Lymphocytic interstitial pneumonia (LIP) is an uncommon histopathologic entity characterized by infiltration of the interstitium and alveolar spaces of the lung by lymphocytes and other lymphoid elements. An increased incidence of LIP has been seen in the pediatric population, especially in children with acquired immune deficiency syndrome. Our previous study supports the notion that Langerhans cells (LCs) are reservoirs for Epstein-Barr virus (EBV) in lungs of human immunodeficiency virus (HIV) subtype E-infected pediatric LIP. To further understand the pathogenesis of LIP, we studied the relationship between EBV, the suggested causative agent of LIP and HIV-1 capsid protein p24, which play an important role in the interaction with host proteins during HIV-1 adsorption, membrane fusion, and entry in surgical lung biopsy-proven LIP from 9 vertically HIV subtype E-infected pediatric patients. The dominant microscopic feature of LIP demonstrated widespread widening of alveolar septum by mononuclear inflammatory cell infiltrate, mainly composed of mature lymphocytes and plasma cells surrounding airways and expanding to the lung interstitium. EBV-encoded RNA (EBER) in situ hybridization (ISH) and p24 immunohistochemistry, performed on formalin-fixed, paraffin-embedded tissue from open lung biopsy specimens, revealed positive intranuclear EBER signals and intracytoplasmic immunostains for p24 core protein in all 9 LIP cases. By combining ISH and immunohistochemistry, these results suggest that (i) EBV/p24-carrying cells are likely involved in the development of LIP, either directly or indirectly; (ii) LCs and related dendritic cells are the main reservoir of both EBV and HIV subtype E in pediatric LIP and possibly LCs may play an important role in the recruitment of inflammatory cell infiltrates, especially T cells into these tissues; (iii) coexpression of EBV/p24 in bronchioalveolar epithelium supports the hypothesis that these cells serve as a reactivation source for both viruses to achieve greater quantities in alveolar septum and interstitium around bronchioles. These results indicate a strong association between the presence of HIV core protein p24 and expression of EBV RNA transcripts (EBER). Interactions between LCs and related dendritic cells together with T cells are important for effective HIV and EBV replications. The coexpression of both viruses could be related to the evolution of pediatric LIP in HIV subtype E infection.