Diffuse Infiltrative Leucocytosis Syndrome: Characterizing Localized Disease in the Salivary Gland

Diffuse infiltrative lymphocytic syndrome (DILS) a cystic lymphoid hyperplasia of HIV/AIDS is a close phenotypic mimic of Sjogren’s syndrome with regard to: SICCA symptoms, salivary gland enlargement, histology and malignant predisposition. DILS is characterized by persistent circulating CD8+ cells and visceral lymphocytic infiltrates. HIV associated salivary gland disease (HIVSGD) reflects a DILS manifestation localized to the major and minor salivary glands. Often an early manifestation of HIV and AIDS defining in pediatric HIV, HIVSGD has also been detected at increased incidence post ART administration. Evidence detailing HIVSGD epidemiology suggests the involvement of a viral opportunist in its pathogenesis. We hypothesized that HIVSGD was a manifestation of DNA tumor virus primary infection/reactivation. In patients clinically diagnosed with HIVSGD, BK viremia, BK shedding and/or BK viral gene products were detected within HIVSGD. An invitro model system was developed that demonstrated BKV productive infection of salivary gland cell lines. To gain insight into the molecular events involved in HIV SGD, suppression subtraction hybridization (SSH), cDNA microarray analysis and real time reverse transcriptase polymerase chain reaction were performed. These analyses revealed the global gene expression profile in HIV SGD. Genes were clustered according to expression pattern using self-organizing map analysis and showed global features of function-related regulation. With consistent detection of the BKV oncoprotein T antigen and its binding partner and p53, accordingly, a unique pattern of modulation was seen in the expression of genes modulated by p53. Further, a unique transcript, MALAT1 was consistently upregulated. We thus demonstrated that BKV detection in HIVSGD, and associated plasma, and in oral fluids. Further, BKV permissive infection in-vitro has been demonstrated suggesting the potential for BKV oral transmission and pathogenesis. Differential gene expression analysis demonstrated the complexity of the HIVSGD gene expression profile providing significant insight to the pathogenesis of the disease.

Studies funded by: 1 R03 DE14444-01, ACTG/NIDCR OHARA 1 U01 AI068636-01/BRS-ACURE-Q-06-00160.T002-002.