CXCR4-using HIV-1 was previously shown to replicate more efficiently in a healthy donor-derived CD4(+) CD38(+) than in a CD4+ CD38(-) T-cell subset after stimulation with interleukin(IL)-4. Here, we identified 3 cellular genes, which were expressed to a higher level in an IL-4-stimulated CD38(-) subset. One of the 3 genes, RNF125/TRAC-1, was involved in the down-regulation of HIV-1 replication not only in cell lines, but also in peripheral blood mononuclear cells. RNFI25/TRAC-1 bears the RING finger domain, important for E3 ubiquitin protein ligase. Mutations in this domain of RNFl25/TRAC-1 led to the loss of HIV-1 down-modulatory activity, suggesting that E3 ligase activity is necessary. In addition, the results of Northern blotting and reporter gene analysis indicated that RNFl25/TRAC-1 function occurs at the viral transcription step. These results suggest that RNFI25/TRAC-1 could function to recruit host factor(s) controlling HIV-1 transcription to the ubiquitin-proteasome pathway. (C) 2007 Elsevier Inc. All rights reserved.