The Bel-1 protein of human foamy virus (HFV) is a transactivator acting on the U3 region of the long terminal repeat and on an internal promoter (IP) immediately upstream of the bel genes. An HFV transgene called delta gpe, containing both promoters and all bel genes, is expressed in the central nervous system and induces neurodegeneration in mice. To dissect the role of individual promoters and bel genes on transgene expression and neurotoxicity we generated transgenic mice with a construct termed pL-bel1, which lacks the IP and the ancillary genes except bel-1. L-bel1 mice transcribed the HFV transgene in more tissues than delta gpe mice, suggesting that CNS specificity is dictated by cis-acting elements not present in the pLbel-1 construct. Unlike delta gpe mice, L-bel1 mice did not develop neurodegenerative changes and did not show induction of nitric oxide synthase expression, although both strains expressed Bel-1 in the brain. Therefore, Bel-1 expression is not sufficient for neurotoxicity. Our results suggest that Bet, a fusion protein between bel-1 and bel-2 which is highly expressed in delta gpe but not in L-bel1 mice, is a candidate for neurotoxicity.