Background:  HIV patients frequently show abnormal B-lymphocyte function, such as hyper-gammaglobulinemia, B-ell hyperactivation and the loss of immune responses to common recall antigens. B-cell lymphoma is the second most prevalent cancer associated with HIV and hyperactivation and hyper-gammaglobulinemia are linked to its genesis. Virions and virus proteins impair B-cell function in vitro, as do cytokines whose expression is altered in HIV infection, although evidence to indicate that these account for all manifestations of B-lymphocyte dysfunction is incomplete and their correlation to patient data is poor.

Methods:  Macrophages infected with HIV-1 or expressing Nef from a viral vector were used to identify soluble factors that altered autologous B-cell function. The properties of these factors were compared in vitro to the abnormalities associated with HIV in vivo. Plasma samples were quantified by ELISA and results analyzed by Mann-Whitney T-Test. Gene arrays demonstrated the molecular responses of B cells.

Results:  HIV-1 infected macrophages drive B-cell dysfunction by the release of a protein with novel immunological properties, Ferritin light chain. Viral replication in macrophages-induced Ferritin and this was dependent on Nef expression. Ferritin, or supernatants from infected macrophages containing Ferritin, caused B-lymphocyte proliferation, differentiation and the production of multiple immunoglobulin subtypes. Ferritin promoted B lymphocytes to enter the cell cycle consistent with known mitogens and was a growth factor for a number of B-cell leukemia cultures. A statistical correlation between viral load, ferritin and hyper-gammaglobulinemia was present in a patient cohort (n = 42; p = 0.0001). However, SIV- infected macaques or sooty mangabeys do not show significant B-cell dysfunction and, correspondingly, they exhibited no raised plasma Ferritin, hyper-gammaglobulinemia, or relationship to viral load. Ferritin was not induced by SIV replication or SIV Nef in vitro.

Conclusions:  The production of ferritin by HIV-1 infected macrophages and the novel immunological properties of ferritin offer a greater understanding of the mechanism of B-cell dysfunction. These findings provide additional evidence on the significance of macrophages in HIV infection and further support Nef as a major pathogenesis factor in HIV disease.

Keywords: B Lymphocyte; Pathogenesis; Nef