Modulation of TRIM5α Activity in Human Cells by Alternatively Spliced TRIM5 Isoforms

TRIM5 alpha is a restriction factor that can block an early step in the retroviral life cycle by recognizing and causing the disassembly of incoming viral capsids, thereby preventing the completion of reverse transcription. Numerous other isoforms of human TRIM5 exist, and isoforms lacking a C-terminal SPRY domain can inhibit the activity of TRIM5 alpha. Thus, TRIM5 alpha activity in a given cell type could be dependent on the relative proportions of TRIM5 isoforms expressed, but little information concerning the relative expression of TRIM5 isoforms in human cells is available. In this study, we demonstrate that mRNAs coding for TRIM5 alpha represent only 50% of total TRIM5 transcripts in human cell lines, CD4(+) T cells, and macrophages. Transcripts coding for, in order of abundance, TRIM5 iota (TRIM5-iota), a previously uncharacterized isoform, TRIM5 gamma, TRIM5 delta, and TRIM5 kappa are also present. Like TRIM5 gamma and TRIM5 delta, TRIM5 delta and TRIM5 kappa do not inhibit HIV-1 replication, but both have dominant-negative activity against TRIM5 alpha. Specific knockdown of TRIM5 iota increases TRIM5 alpha activity in human U373-X4 cells, indicating that physiological levels of expression of truncated TRIM5 isoforms in human cells can reduce the activity of TRIM5 alpha.