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
Brodie, S.J.; Sasseville, V.G.; Reimann, K.A.; Simon, M.A.; Sehgal, P.K.; Ringler, D.J.
Journal of Immunology 153(12): 5790-5801
1994
ISSN/ISBN: 0022-1767 PMID: 7989775 Document Number: 431059
Infection of macrophages (M-vphi) in vitro with M-vphi-tropic isolates of simian immunodeficiency virus (SIV) did not affect killing of Cryptococcus neoformans up to 16 days after inoculation (p lt 0.05). Conversely, alveolar M-vphi from animals with SIV-induced AIDS killed C. neoformans less efficiently (10.4 +- 2.8% killing) and, when stimulated with phorbol myristate, produced less superoxide anion (O-2-; 0.15 +- 0.02 O-2-/h/mg M-vphi protein) than M-vphi from uninfected monkeys (21.8 +- 1.6% killing and 0.29 +- 0.02 O-2-/h/mg M-vphi protein). In contrast, killing and O-2- release were accentuated in SIV+ asymptomatic animals (25.8 +- 2.3% killing and 0.40 +- 0.04 O-2-/h/mg M-vphi protein; p lt 0.05). M-vphi-mediated killing and O-2- production could 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 bioactivity (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). Functional 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 inactivity of supernatants from mitogen-stimulated PBMC cultures derived from animals with AIDS was not solely dependent upon the loss of CD4+ lymphocytes, inasmuch as purified pulmonary alveolar and peripheral blood CD4+ T cells from only uninfected and SIV+ asymptomatic animals, and not those from animals with AIDS, produced IFN-gamma upon mitogen stimulation. Collectively, these findings suggest that functional aberrations in alveolar M-vphi from animals with AIDS are not directly due to virus infection but likely result from changes in the pulmonary microenvironment in association with the multisystemic loss and dysfunction of CD4+ T cells.