Relationship of cell bearing EBER and p24 antigens in biopsy-proven lymphocytic interstitial pneumonia in HIV-1 subtype E infected children.

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.

Cell reservoirs of the Epstein-Barr virus in biopsy-proven lymphocytic interstitial pneumonitis in HIV-1 subtype E infected children: identification by combined in situ hybridization and immunohistochemistry.

Lymphoid interstitial pneumonitis (LIP), a frequent pulmonary complication in human immune deficiency virus (HIV)-infected pediatric patients, is characterized histologically by marked infiltration of lymphoid cells. Several theories have been suggested that LIP may be caused by Epstein-Barr virus (EBV). To identify the reservoir of EBV and pathogenesis of lymphoid infiltrates in HIV subtype E infected pediatric LIP, we examined the distribution and expression of EBV in the inflammatory cell recruitment 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, performed from paraffin-embedded lung tissues, revealed positive intranuclear signals in all 9 LIP cases. Interestingly, combined immunohistochemical and in situ hybridization analyses in 6 out of 9 LIP cases revealed 30% to 50% of the Langerhans and related dendritic cells were infected with EBV, whereas <30% of the T and B cells were infected with EBV. These results suggested that a chronic antigenic stimulus of EBV played important roles in the pathogenesis of LIP in these patients. This supports the notion that Langerhans cells (LCs) are more readily infected with EBV, indicating that LCs are reservoirs for EBV in lungs of HIV subtype E-infected pediatric LIP. And possibly LCs may play an important role in the recruitment of inflammatory cell infiltrates, especially T cells into these tissues. In addition, HIV may provide a milieu or microenvironment for the evolution of LIP, which represent an immunologic response to EBV infection. Interactions between LCs and related dendritic cells together with T cells are important for effective HIV and EBV replications.