In defense of the cell: TRIM5alpha interception of mammalian retroviruses.

Abstract

In the kingdom of the cell, TRIM5α is the arrow of Paris. The genomes of humans and mice attest to a parasitic onslaught of retroviral infections over the millennia (1, 2). In several reports in this issue of PNAS (3–5) and another in press (6), it has become apparent that an ancient and potent antiviral defense meets mammalian retroviruses that elude adaptive immune responses and transgress the cell membrane barrier. Seeking a strategic weakness in the virion coat, TRIM5α targets invading retroviruses for destruction. Whereas a recent breakthrough identified TRIM5α as a HIV-1 restrictive factor expressed by rhesus monkey cells (7), these new findings reveal that human and nonhuman primate TRIM5α can also neutralize other lentiviruses and murine leukemia virus (MLV), a distantly related gammaretrovirus (3–6). In addition, one group discovered that certain MLV isolates are also restricted by primate TRIM1 (3). In the space of a few months, a potentially vast intracellular antiviral network is rapidly coming to view. Intracellular antiviral responses represent the last line of defense in preventing infection of a host organism by retroviruses. Evidence of a specific antiretroviral response was first provided by studies of MLV replication in mouse cells of different genetic backgrounds. Expression of distinct alleles of the mouse Friend virus susceptibility factor-1 ( Fv1 ) locus dictated susceptibility to infection by B- or N-tropic MLV (8–11). Prototypical alleles, such as Fv1-B , restrict infection by N-MLV at an early postentry step, whereas cells expressing Fv1-N restrict infection by B-MLV. Fv1-tropism is determined by a small number of residues in the MLV capsid protein, with a single change in residue 110 sufficient to confer sensitivity to Fv1-B or Fv1-N (12). Fv1 is present in limiting amounts in mouse cells and can be overwhelmed by saturating amounts of challenge …