How TRIM5α defends against retroviral invasions

Abstract

The immune response to viral infections comes in two well described flavors. First, innate immunity [for example, natural killer (NK) cells and IFN responses] nonspecifically recognizes viral infections to trigger autocrine and paracrine signals that limit viral replication. Second, adaptive immunity (for example, T cells and B cells) specifically recognizes viral infections through secreted and cell-meditated factors. However, for retroviral infections, there is a third component of viral recognition and subsequent restriction that has been called “intrinsic immunity” (1). Intrinsic immunity differs from innate and adaptive immunity in that it is cell autonomous (does not rely on secreted factors), it is present in many cells (rather than only in specialized immune cells), it does not need to be induced by viral infections, and it probably evolves with viral infections on a longer evolutionary time scale than the innate and adaptive immune responses. Trim5α is a cytoplasmic protein that forms part of the intrinsic immune system that restricts retroviral infections in primates. This protein targets the viral capsid (CA) protein in a species-specific manner, but the mechanism of how Trim5α inhibits retroviral infections has been unclear. In this issue of PNAS, Stremlau et al. (2) address this important question by showing that Trim5α from rhesus macaques inhibits HIV type 1 (HIV-1) by direct recognition of the viral capsid protein followed by accelerated “uncoating” of capsid from the incoming viral particle. The importance of the Trim5 α gene was originally discovered by the Sodroski laboratory because it protects cells derived from Old World monkeys (OWM) from infection by HIV-1 (3). This gene encodes a protein that is a member of the tripartite motif family defined by the presence of RING, B-box 2, and coiled-coil domains (4, 5). In addition, Trim5α is part of the subset of this family that also contains … *E-mail: memerman{at}fhcrc.org