HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 INFECTION OF HUMAN MACROPHAGES MODULATES THE CYTOKINE RESPONSE TO PNEUMOCYSTIS-CARINII

The present studies examined production of the cytokines tumor necrosi s factor alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and IL-6 b y human monocyte-derived macrophages exposed to Pneumocystis carinii i n vitro and the impact of concurrent macrophage infection with human i mmunodeficiency virus type 1 (HIV-1) on these cytokine responses. Macr ophages were infected with the HIV-1 Bat monocytotropic strain for 10 to 14 days and then exposed to P. carinii. At various times following P. carinii treatment, culture supernatants were harvested to assess th e cytokine profile. Addition of P. carinii to HIV-uninfected macrophag es resulted in augmented production of IL-6, TNF-alpha, and IL-1 beta protein. By contrast, in HIV-infected macrophages exposed to P. carini i, only the release of IL-6 was increased compared with that for HIV-u ninfected macrophages, while the levels of TNF-alpha and IL-1 beta dec reased. This altered response was confirmed at the molecular level for TNF-alpha mRNA. Preventing physical contact between P. carinii and ma crophages by a membrane filter inhibited all cytokine release. Substit uting P. carinii with a preparation of P. carinii 95- to 115-kDa major membrane glycoprotein A yielded a response similar to that obtained b y addition of intact P. carinii. These results suggest that HIV-1 infe ction of human macrophages modulates cytokine responses to P. carinii.