Animal cells have developed many ways to suppress viral replication, and viruses have evolved diverse strategies to resist these. Here we provide evidence that the virion infectivity factor protein of human immunodeficiency virus type 1 (HIV-1) functions to counteract a newly discovered activity in human cells that otherwise inhibits virus replication. This anti-viral phenotype is shown by human T cells, the principal in vivo targets for HIV-1, and, based on our present understanding of virion infectivity factor action, is presumed to act by interfering with a late step(s) in the virus life cycle. These observations indicate that the inhibition of virion infectivity factor function in vivo may prevent HIV-1 replication by 'unmasking' an innate anti-viral phenotype.