To assess the helper T cell dependence of B lymphocyte stimulator (BLyS) protein-driven autoantibody production in vivo, serum levels of BLyS protein, total IgG, and anti-IgG anti-phospholipid (aPhL) autoantibodies from HIV-infected patients (n = 105) with varying degrees of CD4+ cell depletion and healthy control donors at low risk for HIV (n = 64) were determined. Peripheral blood mononuclear cells from these subjects were stained for surface expression of BLyS protein. Monocyte surface expression and serum levels of BLyS protein were increased in HIV-infected patients as were serum total IgG and IgG aPhL autoantibody levels. No associations were detected between increased serum BLyS protein levels and patient age, sex, disease duration, history of opportunistic infection or malignancy, or serum total IgG levels. However, serum levels of IgG aPhL autoantibodies were greater in patients with high serum BLyS protein levels than in those with normal serum BLyS protein levels. Importantly, this association between serum levels of BLyS protein and IgG aPhL was appreciated only in patients who were not severely CD4+ cell-depleted and not in patients who were severely CD4+ cell-depleted (peripheral blood CD4+ cell counts <or= 200/mm(3)). Thus, BLyS protein may preferentially facilitate IgG autoantibody production in vivo in a helper T cell-dependent manner. This raises the possibility that the combination of a BLyS protein antagonist with an agent that targets (helper) T cells may have salutary synergistic effects on autoantibody production in diseases such as systemic lupus erythematosus.