TRIM5 is a capsid-specific restriction factor that blocks retroviral replication early in the post-entry phase, before reverse transcription 1. The protein recognizes viral capsids through its PRYSPRY domain, which determines viral specificity and restriction potency 2. Upon capsid binding, TRIM5's RING domain and B-box 2 domain trigger E3 ubiquitin ligase activity, generating K63-linked polyubiquitin chains that activate the MAP3K7/TAK1 complex and induce NF-κB and MAPK-dependent inflammatory gene expression 1. TRIM5 restricts diverse retroviruses including N-MLV, EIAV, SIVmac, FIV, and BIV 2. Additionally, TRIM5 functions as a pattern recognition receptor for innate immune activation and regulates autophagy by targeting viral capsid proteins, including HIV-1 p24 3. Recent studies demonstrate TRIM5 also restricts orthopoxviruses via SPRY domain-L3 protein interactions, with cyclophilin A antagonizing this restriction 4. Clinically, natural human TRIM5α variants poorly restrict HIV-1, but engineered mutations (R332G/R355G) confer HIV-1 resistance 5. TRIM5 is implicated in vascular disease pathology, where Nrf3-mediated upregulation promotes autophagy and neointimal hyperplasia 6. These findings support TRIM5 as a multifunctional innate immune factor with therapeutic potential for retroviral and DNA virus infections.