Mannoprotein-Induced Anti-U937 Cell Cytotoxicity in Peripheral Blood Mononuclear Cells from Uninfected or HIV-Infected Subjects: Role of Interferon-γ and Tumor Necrosis Factor-α

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-I) 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-I 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-1β, IL-6, TNF-α, GM-CSF, and IFN-γ production was analyzed. Decreases in TNF-α, GM-CSF, and IFN-γ, but not IL-1β 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-γ 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-γ production plays a role in the abrogation of U937-MAK activity: (i) addition of neutralizing anti-IFN-γ antibodies abolished both IFN-γ and U937-MAK activity in PBMC from healthy subjects: (ii) substantial levels of IFN-γ were detected in supernatants of PBMC cultures stimulated by IL-2, in line with preserved U937-LAK activity. Interestingly, anti-IFN-γ antibodies also abolished TNF-α production, and the anti-TNF-α effect was comparable to that of anti-IFN-γ in U937-MAK inhibition. In contrast, anti-TNF-α antibodies abrogated TNF-α activity, but only partially reduced IFN-γ 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-γ in U937 MAK activity, possibly through activation of TNF-α production.