[Proceedings, Annual Meeting of the Laboratory of Tumor Cell Biology (1990 : Bethesda, Maryland)]

Spontaneous TNF-a and IL-6 secretion by B-lymphocytes from HIV Infected
Individuals contribute to virus expression In infected T cells and monocytes
P. Rieckmann, G. Poll, J.H. Kehrl, A.S. Fauci; Laboratory of Immunoregulation,
NIAID, NIH, Bethesda, USA
Hypergammaglobulinemia and polyclonal B cell activation are common features in patients
infected with HIV. Since it has been shown that cytokines such as tumor necrosis factor
alpha (TNF-a) and interleukin 6 (IL-6) induce HIV expression in infected cells and that in
vitro activated B-lymphocytes synthesize both TNF-a and IL-6, we investigated the potential
role of cytokine production by B cells in HIV expression. Highly purified B-lymphocytes from
HIV infected individuals were found to spontaneously secrete significantly greater amounts
of IL-6 (7 = 536 pg/ml vs. 18 pg/ml) and TNF-a (x = 493 pg/ml vs. 23 pg/mI) than B cells
isolated from normal seronegative donors. In vitro stimulation of the B cells from the
normal donors resulted in the secretion of TNF-a and IL-6 levels comparable to those found
in the supematants from unstimulated patients' B cells. In addition, B cells from HIV
infected individuals in contrast to B-lymphocytes from normal donors were shown to induce
virus expression in two cell lines: ACH-2, a T cell line and U1, a promonocytic cell line,
which are chronically infected with HIV. In all patients (10/10) with hypergammaglobulinemia (IgG > 1600 mg/dl) spontaneous HIV inductive capacity was found with highly purified
peripheral blood B-lymphocytes in direct co-culture experiments with the infected cell lines
or in experiments with B cell culture supematants and the infected cells. B cell TNF-a and
IL-6 production was shown to be important in the induction of HIV expression in these
experiments since antibodies against both cytokines abolished it. Furthermore, an anti-IL-6
antibody also inhibited the spontaneous immunoglobulin production by B cells from HIV
infected individuals. Finally, in a subset of patients (5/9) but in none of the normal controls
recombinant gp120 was shown to further stimulate cytokine production and HIV inductive
capacity of the B cells suggesting an important role for viral products in the stimulation of
TNF-a and IL-6 production by B-lymphocytes in vivo. These studies implicate cyokine
production by B cells as an important factor in the pathogenesis of HIV infection.