MOLECULAR ANALYSIS OF IMMUNOGLOBULIN VARIABLE GENES IN HIV-RELATED NON HODGKIN LYMPHOMA REVEALS IMPLICATIONS FOR DISEASE PATHOGENESIS AND HISTOGENESIS

BACKGROUND: Human immunodeficiency virus (HIV)-related non-Hodgkin's lymphomas (HIV-NHL) are heterogeneous and associated with distinct molecular pathways. Analysis of immunoglobulin variable genes (IGV) may provide insights into the pathogenesis and histogenesis of HIV-NHL. DESIGN AND METHODS: IGV rearrangements were amplified from genomic DNA by polymerase chain reaction and directly sequenced in 87 cases of HIV-NHL (17 Burkitt/Burkitt-like lymphomas, 38 diffuse large B-cell lymphomas, and 32 primary central nervous system lymphomas). RESULTS: A skewed IGHV repertoire in specific HIV-NHL clinico-pathological categories was observed. Systemic HIV-diffuse large B-cell lymphomas displayed underrepresentation of the IGHV3 family (11/38, 28.9%; p=0.0047) and, in particular, of the IGHV3-23 gene (0/38; p<0.001). These same cases were also characterized by significant overrepresentation of the IGHV4 family (18/38; 47.4%; p=0.0044) and, in particular, of the IGHV4-34 gene (10/38; 26.3%; p=0.003). HIV-primary central nervous system lymphomas displayed a preferential usage of IGLV6-57, with stereotyped B-cell receptor in two cases. Somatic hypermutation of IGHV genes was detected in 81/87 (93.1%) HIV-NHL. Unmutated cases were restricted to six HIV-primary central nervous system lymphomas with immunoblastic plasmacytoid morphology. A mutational profile suggesting a tendency to maintain antigen binding and antigen selection was observed in more than 50% of the cases of IGV mutated HIV-NHL. CONCLUSIONS: Our data show evidence of a skewed IGHV repertoire in specific HIV-NHL categories and suggest B-cell receptor restriction in some HIV-primary central nervous system lymphomas. The heterogeneous representation of IGHV genes in HIV-NHL may be related to specific pathways of antigen stimulation, or to differences in host's immune dysregulation and lymphoma histogenesis.