V_HGene Use by HIV Type 1-Associated Lymphoproliferations

Abstract

The pathogenesis of polyclonal HIV-associated lymphomas lacking traditional B cell cofactors (i.e., Epstein-Barr virus [EBV] infection, c-myc translocations) is poorly understood. A multistep pathogenesis model has been proposed in which polyclonal lymphomas represent an earlier stage in HIV-associated lymphomagenesis before the emergence of a dominant malignant clone. Chronically present antigens have been proposed as a likely stimulus for polyclonal B cell proliferation; if so, polyclonal lymphoma-associated immunoglobulins (Igs) should have molecular evidence of somatic hypermutation, a process by which antibody affinity maturation in response to chronic antigenic stimulation occurs. Molecular analyses of Ig heavy chain variable (V(H)) gene use by B cells in a polyclonal HIV-associated large cell lymphoma lacking EBV and c-myc rearrangement was undertaken. Eighteen randomly selected clones generated from RT-PCR yielded 15 unique V(H) sequences, all of which were most homologous to only three previously identified germline V(H)1 genes. Two sets of clones (consisting of three and two clones, respectively) had identical V(H) gene sequences, and one pair of clones had identical third complementarity determining regions (CDR3s) but different V(H) gene sequences; eight clones were <95% homologous to their most related germline V(H)1 genes. We compared these results with Ig V(H)1 gene use by B cells present in a reactive hyperplastic lymph node obtained from an HIV-1-infected individual. Fifteen clones randomly selected from RT-PCRs yielded 15 unique V(H)1 sequences, all of which were most homologous to 5 previously identified germline V(H)1 genes; 10 clones were <95% homologous to their most related germline gene. Binomial probability analysis revealed that only 1 of the 15 unique V(H)1 sequences derived from the polyclonal lymphoma (i.e., 7%), as compared with 5 of 15 unique V(H)1 sequences derived from the reactive lymph node (i.e., 33%), had a low probability of occurrence by random chance (p < 0.05). These data provide molecular evidence of polyclonality in an HIV-associated polyclonal lymphoma, demonstrate a qualitative difference in somatic hypermutations of Ig V(H) genes associated with malignant versus reactive B cell lymphoproliferations, and support an antigen-mediated multistep pathogenesis model of HIV-1-associated lymphomagenesis.

Selective deficit in antibodies specific for the superantigen binding site of gp120 in HIV infection

“…Anti-HIV antibodies of the IgA isotype have been shown to possess neutralizing activity in vitro (36,37). These alterations are reminiscent of previous reports showing that the V H 3 gene family is underrepresented in several compartments of the immune system of HIV-1-seropositive individuals, including peripheral blood (11,13), bone marrow (38), lymph node, and spleen (12,39).…”

HIV-1 Nef in Macrophage-Mediated Disease Pathogenesis

“…Swingler and colleagues [76] have also described an intricate relationship between Nef, macrophages and B-cells, indicating that the HIV-1 Nef protein carries a pathogenic determinant that governs B-cell defects in HIV-1 infection. Antigenic stimulation of B-cells by activated macrophages plays a central role in the pathogenesis of ARL [17, 77, 78]. HIV-1 Nef has been directly implicated in B-cell activation via production of soluble factors such as IL-2 and IL-6 and elevation of immunoglobulin [76].…”