MACROPHAGE FUNCTION IN SIMIAN AIDS - KILLING DEFECTS IN-VIVO ARE INDEPENDENT OF MACROPHAGE INFECTION, ASSOCIATED WITH ALTERATIONS IN TH PHENOTYPE, AND REVERSIBLE WITH IFN-GAMMA

Infection of macrophages (M phi) in vitro with M phi-tropic isolates o f simian immunodeficiency virus (SIV) did not affect killing of Crypto coccus neoformans up to 16 days after inoculation (p < 0.05). Converse ly, alveolar M phi from animals with SIV-induced AIDS killed C. neofor mans less efficiently (10.4 +/- 2.8% killing) and, when stimulated wit h phorbol myristate, produced less superoxide anion (O-2(-); 0.15 +/- 0.02 O-2(-)/h/mg M phi protein) than M phi from uninfected monkeys (21 .8 +/- 1.6% killing and 0.29 +/- 0.02 O-2(-)/h/mg M phi protein). In c ontrast, killing and O-2(-) release were accentuated in SIV+ asymptoma tic animals (25.8 +/- 2.3% killing and 0.40 +/- 0.04 O-2(-)/h/mg M phi protein; p < 0.05). M phi-mediated killing and O-2(-) production coul d be restored by culturing the affected cells in supernatants derived from Con A-stimulated PBMC of uninfected or SIV+ asymptomatic monkeys. Supernatants with restorative properties had high IFN-gamma bioactivi ty (63.4 +/- 11.0 U/ml) and elevated IL-10 concentrations (75.3 +/- 10 .4 pg/ml) as compared with PBMC supernatants derived from animals with AIDS (IFN-gamma, 9.7 +/- 4.9 U/ml; IL-10, 24.0 +/- 10.1 pg/ml). Funct ional restoration was found to be dependent, in part, on the presence of IFN-gamma, as neutralizing Abs to IFN-gamma significantly inhibited functional restoration in active supernatants. Moreover, the inactivi ty of supernatants from mitogen-stimulated PBMC cultures derived from animals with AIDS was not solely dependent upon the loss of CD4(+) lym phocytes, inasmuch as purified pulmonary alveolar and peripheral blood CD4(+) T cells from only uninfected and SIV+ asymptomatic animals, an d not those from animals with AIDS, produced IFN-gamma upon mitogen st imulation. Collectively, these findings suggest that functional aberra tions in alveolar M phi from animals with AIDS are not directly due to virus infection but likely result from changes in the pulmonary micro environment in association with the multisystemic loss and dysfunction of CD4(+) T cells.