Removal of Arginine 332 Allows Human TRIM5α To Bind Human Immunodeficiency Virus Capsids and To Restrict Infection

Abstract

ABSTRACT Human TRIM5α (TRIM5α hu ) only modestly inhibits human immunodeficiency virus type 1 (HIV-1) and does not inhibit simian immunodeficiency virus (SIV mac ). Alteration of arginine 332 in the TRIM5α hu B30.2 domain to proline, the residue found in rhesus monkey TRIM5α, has been shown to create a potent restricting factor for both HIV-1 and SIV mac. Here we demonstrate that the potentiation of HIV-1 inhibition results from the removal of a positively charged residue at position 332 of TRIM5α hu. The increase in restricting activity correlated with an increase in the ability of TRIM5α hu mutants lacking arginine 332 to bind HIV-1 capsid complexes. A change in the cyclophilin A-binding loop of the HIV-1 capsid decreased TRIM5α hu R332P binding and allowed escape from restriction. The ability of TRIM5α hu to restrict SIV mac could be disrupted by the presence of any charged residue at position 332. Thus, charged residues in the v1 region of the TRIM5α hu B30.2 domain can modulate capsid binding and restriction potency. Therapeutic strategies designed to neutralize arginine 332 of TRIM5α hu might potentiate the innate resistance of human cells to HIV-1 infection.