TRIM5alpha: An intracellular defense against retroviruses

Host cell barriers to the early phase of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) replication explain the current distribution of these viruses among human and non-human primate species. HIV-1 encounters a post-entry block in cells from Old World monkeys whereas SIV encounters a block in most New World monkey cells. Restriction is mediated by dominant host factors that target the viral capsid. The block occurs prior to or concurrent with reverse transcription, and prevents the accumulation of full-length viral cDNA.; From a genetic screen we identified TRIM5alpha as a primary determinant of the block to HIV-1 infection in Old World monkey cells. TRIM5alpha contains a tripartite motif (TRIM) consisting of a RING domain, B-box 2 domain, and a coiled-coil domain. TRIM5alpha is the longest of the TRIM5 isoforms and the only one to contain a carboxy-terminal B30.2 domain. We show that rhesus monkey TRIM5alpha (TRIMalpharh) potently blocks HIV-1, but only modestly inhibits SIV, and does not restrict MLV. TRIM5alpharh targets the HIV-1 capsid and prevents the formation of full-length reverse transcripts. Transfection of TRIM5alpha-specific small interfering RNA (siRNA) into primary rhesus monkey cells relieves the block to HIV-l. Thus, TRIM5alpha is necessary and sufficient for HIV-1 restriction in rhesus monkey cells.; Human TRIM5alphaTRIM5alphahu) modestly blocks HIV-1 accounting for the differences in species-specific restriction of HIV-1. The determinants of antiviral potency between TRIM5alphahu and TRIM5alpha rh map to the B30.2 domain. We show that changes at a single residue in the B30.2 domain (332) dramatically enhance the antiviral potency of TRIM5alpha hu.; To study the interaction between the HIV-1 capsid and TRIM5alpha, we developed a novel binding assay. We show that TRIM5alpha variants from Old World monkey species specifically associate with the HIV-1 capsid and that this interaction depends on the B30.2 domain. Human and New World monkey TRIM5alpha associate less efficiently with the HIV-1 capsid, accounting for the lack of restriction in cells of these species.; The antiviral mechanism of TRIM5alpha is unknown. To study the effects of the association between TRIM5alpha and the HIV-1 capsid, we designed a novel assay to follow the fate of soluble and particulate capsids in infected cells. We show that the expression of a restricting TRIM5alpha correlates with a decrease in the amount of particulate capsid recovered from the cytosol of infected cells. In some cases, this loss of particulate capsid is accompanied by a detectable increase of soluble capsid protein. These results suggest that TRIM5alpha restricts retroviral infection by specifically recognizing the capsid core and promoting its rapid, premature disassembly.