Background: AIDS-related non–Hodgkin lymphoma (AIDS-NHL) is a common AIDS-defining cancer. Prior studies suggest that chronic B-cell activation precedes AIDS-NHL diagnosis. Activation of B cells by multiple factors, including Toll-like receptor (TLR) signaling, leads to the expression of activation-induced cytidine deaminase (AID), a DNA mutating molecule that can contribute to oncogene translocations/mutations, leading to NHL. The goal of this study was to determine whether surface markers expressed on activated and/or germinal center B cells, and AID expression, were elevated on circulating B cells preceding AIDS-NHL and to determine if TLR signaling contributes to this activated B-cell phenotype.
Methods: Stored viable peripheral blood mononuclear cell specimens, obtained before AIDS-NHL diagnosis, were assessed by multicolor flow cytometry. Additionally, B cells isolated from peripheral blood mononuclear cell were exposed to TLR ligands in vitro, after which B-cell phenotype was assessed by flow cytometry.
Results: An elevated fraction of B cells expressing CD10, CD71, or CD86 was seen in those who went on to develop AIDS-NHL. AID expression was detected in some who developed AIDS-NHL, but not in HIV+ or HIV− controls. TLR2-stimulated purified B cells exhibited the activated B-cell phenotype observed in HIV+ subjects before AIDS-NHL diagnosis.
Conclusions: These results indicate that an elevated fraction of B cells display an activated/germinal center phenotype in those HIV+ subjects who go on to develop AIDS-NHL and suggest that TLR2-mediated activation may play a role in HIV infection–associated B-cell activation, potentially contributing to the genesis of AIDS-NHL.
*UCLA AIDS Institute, Los Angeles, CA;
†The Institution of Viral disease Control and Prevention, CDC, Beijing, China;
‡Departments of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, CA;
§Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL;
‖Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA;
¶Department of Epidemiology, UCLA Jonathan and Karin Fielding School of Public Health, Los Angeles, CA; and
#Jonsson Comprehensive Cancer Center, Los Angeles, CA.
Correspondence to: Otoniel Martinez-Maza, PhD, UCLA AIDS Institute, BSRB 173, 615 Charles Young Drive South, Los Angeles, CA 90077–7363; email@example.com. Los Angeles, CA.
Supported in part by grants from the NIH (NCI supplement to U01-AI-035040 and R01-CA-168482). Y.G. was a Fogarty Fellow, supported by an award from the University of California, Los Angeles Fogarty AIDS International Training and Research Program (D43-TW-000013). B.S. and A.L.L. were supported by funding from NIH Center for AIDS Research (P30-AI-082151) and P01-AI-076174. This work was carried out in the facilities of the University of California, Los Angeles AIDS Institute, which were supported, in part, by funds from the James B. Pendleton Charitable Trust and the McCarthy Family Foundation.
The authors have no conflicts of interest to disclose.
Received February 15, 2013
Accepted May 23, 2013