INDUCTION OF IFN-ALPHA BY HIV-1 IN MONOCYTE-ENRICHED PBMC REQUIRES GP120-CD4 INTERACTION BUT NOT VIRUS-REPLICATION

IFN-alpha is in plasma of HIV-1 infected patients during early and lat e-stage disease and may play a role in control of virus replication. T he stimulus for IFN-alpha production, the cells that produce this cyto kine, and the effectiveness of this IFN-alpha response for control of virus infection are not yet defined. Culture fluids from freshly isola ted PBMC of HIV-1 seronegative donors contained high levels of IFN-alp ha after exposure to 100 to 1000 infectious HIV-1 particles per cultur e. Levels of IFN-alpha induced by HIV-1 were directly dependent on the number of monocytes in cell preparations: No IFN-alpha was detected f rom T cell-enriched PBMC. In monocyte cultures, induction of IFN-alpha by HIV-1 was relatively specific: Levels of IL-1beta, IL-6, IFN-gamma , and TNF-alpha remained at baseline. Capacity of HIV-1 virions to ind uce IFN-alpha was not dependent on virus replication. IFN-alpha was in duced by (a) heat-inactivated HIV-1, (b) virions from 8E5 cells, a cel l line that releases noninfectious HIV-1, (c) HIV-1-infected cells fix ed in paraformaldehyde, and (d) T cell-tropic HIV-1 that binds to but does not infect monocytes. Capacity of HIV-1 virions and HIV-1 infecte d cells to induce IFN-alpha was completely inhibited by soluble rCD4 o r mAb against CD4 or gp120. Antibodies against CD4, however, did not i nduce monocytes to produce IFN-alpha. HIV-1-induced IFN-alpha producti on was inhibited by antibodies against both V3 loop determinants and t he CD4 binding site of gp120. Further, sera and purified immunoglobuli n from HIV-1 infected patients also inhibited HIV-1-induced IFN-alpha production. These observations suggest that potentially protective ant iviral responses associated with IFN-alpha production in HIV-1 infecte d patients are inhibited by the development of antibodies against gp12 0.