Human foamy virus (HFV) is a recently characterized retrovirus which was originally isolated from patients with various neoplastic and degenerative diseases. However, until today it has not been possible to identify HFV as the causative agent of any disease and little is known about its prevalence in human populations. Like HTLV and HIV, HFV encodes the three structural retroviral genes, gag, pol and env, and an additional region containing three open reading frames, bel-1 to bel-3. Bel-1 activates transcription of the long terminal repeat of HFV and HIV. In order to study the consequences of expressing HFV regulatory genes and to investigate a possible pathogenic potential of HFV, we have introduced parts of the HFV genome into the germ line of mice. Our studies with transgenic mice demonstrate that HFV transgenes encompassing the bel region are transiently transcribed between midgestation and birth at moderate levels in various tissues. Expression is then suppressed, but resumes after a latency of several weeks in a restricted range of tissues and leads to extensive accumulation of HFV transcripts in single cells. This is associated with a progressive degenerative disease of the central nervous system and of striated muscle. These findings provide the first evidence of a disease induced by HFV and suggest that HFV might also act as a human pathogen in neurological diseases. Moreover, the transgenic mouse model will be useful for studying the molecular basis of HFV-induced neurotoxicity, the role of individual disease-associated HFV genes and the regulation of retroviral latency.