Individuals infected by the human immunodeficiency virus (HIV) are at an increased risk for developing B-cell non-Hodgkin's lymphomas (AIDS-NHL). With the introduction of highly active antiretroviral therapy (HAART) in 1996, there has been a significant decline in the overall incidence of AIDS-NHL, especially that of primary central nervous system lymphoma (PCNSL). However, a much smaller decrease in the incidence of other forms of AIDS-NHL has been seen even in the HAART era. Thus, AIDS-NHLs remain a significant cause of morbidity and mortality in HIV infected individuals. Recently, much attention has been directed towards the role of small non-coding microRNAs (miRNA) in cancer, including in NHL. However, the role of miRNAs in B-cell lymphomas in the setting of HIV/AIDS and immunodeficiency is not well understood.

Here we used a miRNA microarray platform to define the miRNA signature of differentiation stage specific B cell subsets—naïve, germinal center (GC), and memory. Using this signature, we identified that the GC overexpressed miR-17-92 paralog cluster miRNAs were also upregulated in various subtypes of AIDS-NHLs, including in Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), PCNSL, and primary effusion lymphoma (PEL). Furthermore, we also show that select miRNAs from these clusters (miR-17, miR-106a, miR-106b) inhibit expression of the cell cycle inhibitor p21/CDKN1A providing a mechanistic role for these miRNAs in AIDS-NHL pathogenesis. Interestingly, we also found that select oncogenic miRNAs including miR-155, miR-21, and miR-17-92 paralogs were upregulated in peripheral B cells of HIV+ individual prior to AIDS-NHL diagnosis. This has profound implications for use of these miRNAs as biomarkers. Additionally, we found that B cells can modulate miRNA expression in response to B cell stimuli like IL4/anti-CD40, IL6, IL10, and lipopolysaccharide (LPS) which are elevated in HIV+ individuals. Finally, we found B-cell activating roles for viral miRNAs (from Epstein-Barr virus, EBV and Kaposi sarcoma associated virus, KSHV) and T cells during HIV infection. In conclusion, our work implicates miRNAs in normal B-cell differentiation, in response to exogenous stimuli, and in the pathogenesis of AIDS-NHLs.