Acquired immunodeficiency syndrome (AIDS) is caused by infection with T-cell tropic retrovirus HIV. The disease is characterized by a profound defect in cell-mediated immunity and a number of serologic abnormalities. Among the serologic abnormalities, the presence of an unusual acid-labile interferon (IFN) has been repeatedly found, and it is considered to be a marker of infection HIV evolving toward illness. Because little is known about the relationships existing between the etiologic agent of AIDS (i.e. HIV) and acid-labile IFN alpha, we approached this problem by testing whether acid-labile IFN alpha is induced in vitro by this virus. In this paper we compared the IFN-inducing activity of free, infectious HIV to that of HIV-infected cells. A number of other enveloped viruses and virus-infected cells were used as controls. Interferon inducing activity by virions as compared to virus-infected cells was determined by incubating human PBMC either with VSV, HSV, and HIV or with cells infected with the same viruses. In this case cells were fixed with glutaraldehyde to prevent virus shedding. While VSV and HSV induced production of acid-stable IFN both as free virions and as virus-infected cells, HIV induced acid-stable IFN when applied as a viral suspension, but it did produce acid-labile IFN when virus-infected cells were used as the inducer. In fact the IFN produced under these circumstances lost more than 80% of its activity when treated to pH2, no matter whether H9/HIV or HIV infected PBMC were used as the inducer. Because acid-lability is a peculiar property of IFN gamma, whereas both native and cloned IFN alpha are completely stable under acid conditions, we compared the IFNs induced by either HIV and HIV-infected cells to standard IFN alpha and gamma preparations with respect to (i) acid stability (ii) neutralization with specific antisera (iii) apparent molecular weight estimated by gel filtration. Results indicate that HIV-induced IFN behaves exactly as standard IFN alpha, as it was completely stable at pH2, totally inactivated by anti-IFN alpha and not by anti-IFN gamma serum, and had apparent molecular weight of 20,000; conversely IFN induced by HIV-infected cells, both H9/HIV and PBMC/HIV, although sharing with IFN alpha both molecular weight and antigenic properties, was inactivated by acid treatment by more than 80%.(ABSTRACT TRUNCATED AT 400 WORDS)