Mannoprotein-induced anti-U937 cell cytotoxicity in peripheral blood mononuclear cells from uninfected or HIV-infected subjects: role of interferon-gamma and tumor necrosis factor-alpha.

A mannoprotein fraction (MP-F2: mannan, > 90%; protein, 4.5%) from the human commensal microorganism Candida albicans was as efficient as interleukin-2 (IL-2) in generating cytotoxicity against the uninfected or human immunodeficiency virus type-1 (HIV-1) persistently infected monocytoid U937 cell line in cultured peripheral blood mononuclear cells (PBMC) from healthy human subjects. MP-F2-activated killing of U937 cells (U937-MAK) decreased progressively with advancing stages of HIV-1 infection to virtually no killing effect in PBMC from advanced AIDS subjects (AIDS PBMC). This decrease paralleled a lowered susceptibility of U937 cells to natural killer cell activity. In contrast, IL-2-activated killing of U937 cells (U937-LAK) was not affected by the progression of HIV infection and persisted at high levels in AIDS PBMC. To shed light on the mechanisms of U937-MAK and its decrease during HIV infection, IL-1 beta, IL-6, TNF-alpha, GM-CSF, and IFN-gamma production was analyzed. Decreases in TNF-alpha, GM-CSF, and IFN-gamma, but not IL-1 beta or IL-6, levels were observed in MP-F2-stimulated PBMC from HIV-infected subjects, compared to healthy controls. Interestingly, these cytokine levels fell before the onset of AIDS. The greatest relative drop was that of IFN-gamma, from 4600 (+/- 600) to 290 (+/- 160) and 217 (+/- 110) mean pg/ml (+/- SE) in PBMC from healthy donors (11 subjects), CDC stages II + III (14 subjects), and CDC stage IV (10 subjects), respectively. The following observations suggest that decreased IFN-gamma production plays a role in the abrogation of U937-MAK activity: (i) addition of neutralizing anti-IFN-gamma antibodies abolished both IFN-gamma and U937-MAK activity in PBMC from healthy subjects; (ii) substantial levels of IFN-gamma were detected in supernatants of PBMC cultures stimulated by IL-2, in line with preserved U937-LAK activity. Interestingly, anti-IFN-gamma antibodies also abolished TNF-alpha production, and the anti-TNF-alpha antiserum effect was comparable to that of anti-IFN-gamma in U937-MAK inhibition. In contrast, anti-TNF-alpha antibodies abrogated TNF-alpha activity, but only partially reduced IFN-gamma production. Thus, in human PBMC, U937-MAK activity progressively decreases with advancing stages of HIV infection, whereas U937-LAK activity is sustained. Furthermore, the present results indicate a pivotal role for IFN-gamma in U937 MAK activity, possibly through activation of TNF-alpha production.