Expression of human foamy virus is differentially regulated during development in transgenic mice

Abstract

The human foamy virus (HFV) is a recently characterized member of the spumavirus family. Although no diseases have been unequivocally associated with HFV infection, expression of HFV regulatory genes in transgenic mice induces a characteristic acute neurodegenerative disease and a myopathy. To better characterize the sequence of events leading to disease, and to gain a better understanding of the underlying pathogenetic mechanisms, we have analyzed in detail the transgene expression pattern during development. Transcription of a construct containing all regulatory elements and ancillary genes of HFV was analyzed by in situ hybridization and was shown to occur in two distinct phases. At midgestation, low but widespread expression was first detected in cells of extraembryonic tissues. Later, various tissues originating from embryonic mesoderm, neuroectoderm, and neural crest transcribed the transgene at moderate levels. However, expression decreased dramatically during late gestation and was suppressed shortly after birth. After a latency period of up to 5 weeks, transcription of the transgene resumed in single cells distributed irregularly in the central nervous system and in the skeletal muscle. By the age of 8 weeks, an increasing number of cells displayed much higher expression levels than in embryonic life and eventually underwent severe degenerative changes. These findings demonstrate that HFV transgene expression is differentially regulated in development and that HFV cytotoxicity may be dose-dependent. Such biphasic pattern of expression differs from that of murine retroviruses and may be explained by the specificity of HFV regulatory elements in combination with cellular factors. Future studies of this model system should, therefore, provide novel insights in the mechanisms controlling retroviral latency.