FIG. 7.
Hypothetical model illustrating the possible implication of CD40L-bearing virions in B-lymphocyte phenotypic and functional alterations in HIV-1 disease. (1) Early after primary infection, HIV-1 concentrates in secondary lymphoid organs, where a high frequency of activated CD4+ T cells are located; (2) production of progeny viruses bearing host-derived CD40L on their surface from newly infected CD4+ T cells, (3) binding of CD40L-bearing virions to B lymphocytes residing within this microenvironment leads to polyclonal B-cell activation, proliferation, and terminal differentiation; (4) as a by-product of B-cell activation, class switch recombination and somatic hypermutation of IgG is induced, leading to the aberrant secretion of IgG and thus hypergammaglobulinemia; (5) CD40-stimulated B cells secrete soluble factors, among which are CCL17 and CCL22; (6) CD4+ T cells are recruited to the secondary lymphoid organs; (7) attracted CD4+ T cells are exposed to both cell-free and B cell-associated viruses in a context of high levels of proinflammatory cytokines and costimulatory factors expressed by CD40-stimulated B cells; (8) activated CD4+ T cells transiently express cell surface CD40L, which then can be acquired by de novo-produced virions, fuelling the feedback loop.