REGULATION OF HIV-1 INFECTION IN ASTROCYTES - EXPRESSION OF NEF TNF-ALPHA AND IL-6 IS ENHANCED IN COCULTURE OF ASTROCYTES WITH MACROPHAGES

'Restricted' human immunodeficiency virus type (HIV-1) infection of as trocytes is recognized in vivo in some pediatric and adult AIDS brains and in vitro in a small proportion of transfected primary fetal astro cytes. We investigated the extent of HIV-1(JR-FL) expression in fetal astrocytes and macrophages cultivated alone or together. Peak HIV-1 p2 4 antigen titres in supernatant fluids of macrophage cultures were inc reased with monocyte/macrophages from certain donors and were higher w hen macrophages were cocultivated with astrocytes. Structural HIV-1 ge ne (gp 41 and pol) products (protein and mRNA) were observed only in m acrophages. Ten days after HIV-1(JR-FL) infection, astrocytes in a mon oculture were stained negative or only weakly positive (1-2+) for Nef, whereas in a coculture up to 100% of astrocytes displayed Nef stainin g (up to 4+) in the cytoplasm. The streptavidine-biotine-peroxidase te chnique with certain monoclonal antibodies to Nef (Ovod et al, 1992) w as specific for infected astrocytes. The intensity of Nef staining was higher in astrocytes cultivated with monocyte/macrophages from certai n donors. In the coculture, tumor necrosis factor-alpha (TNF-alpha) wa s expressed in the astrocyte cytoplasm earlier after coinfection with HIV-1 and cytomegalovirus (CMV) compared to infection with HIV-1 alone . Interleukin-6 (IL-6) was secreted spontaneously and transiently in u ninfected cocultures, but in a prolonged fashion following HIV-1 and H IV-1/CMV infections. The interactions between HIV-1- and CMV-infected macrophages and astrocytes lead to upregulation of TNF-alpha and IL-6 and enhancement of productive HIV-1 infection of macrophages and of 'r estricted' HIV-1 infection of astrocytes with implications for the pat hogenesis of AIDS dementia.