Cell Reservoirs of the Epstein-Barr Virus in Biopsy-proven Lymphocytic Interstitial Pneumonitis in HIV-1 Subtype E Infected Children

Abstract

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.

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

“…30 Immune dysregulation from HIV and latent EBV infection may play a role in the pathogenesis of LIP. 11,31 The relationship between these 2 viruses has been postulated since they have been found in both adults and children with LIP. 32,33 There is an active investigation into the role of EBER and HIV p24 in the pathogenesis of LIP.…”

Noninfectious Pulmonary Complications of Human Immunodeficiency Virus Infection

“…41 The presence of HIV and HIV-related proteins in germinal centers, the pulmonary interstitium and bronchoalveolar lavage fluid of patients with LIP support a direct causative role for the virus 42 in this condition. In contrast, other evidence suggests a role for coinfections in the development of lymphoproliferative pulmonary disease in HIV, including with Epstein–Barr virus, 43 cytomegalovirus 44 and human T-lymphotrophic virus 1. 45 …”

Proteomics of Bronchoalveolar Lavage Fluid Reveals a Lung Oxidative Stress Response in Murine Herpesvirus-68 Infection

“…Moreover, chronic pulmonary diseases such as asthma, COPD, and idiopathic pulmonary fibrosis (IPF) might have an infectious viral component to their onset and/or pathogenesis. The gammaherpesviruses Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV-8) and Epstein–Barr virus (EBV) have been detected in the lung tissue of patients with IPF and acquired immune deficiency syndrome (AIDS)-related lymphocytic interstitial pneumonias [12,13,14]. In contrast, a murine gammaherpesvirus is protective in mice challenged with lethal influenza A virus, suggesting immunomodulatory roles for gammaherpesviruses in the pathogenesis of lung infections [14].…”