The search for novel modulator of HIV-1 and more generally, virus infection is a key step towards the understanding of host pathogen interactions that allow or oppose infection. To highlight novel cellular modulators of HIV-1 infection in macrophage-like cells, we have carried out a functional/evolutionary screen and we have identified the Tripartite Motif Protein 69 (Trim69), a poorly studied member of the Trim family, that includes a large spectrum of innate immunity regulators. Trim69 inhibits not only all the primate lentiviruses tested, but also the replication of VSV and SARS-CoV2, highlighting it as a broad antiviral protein. By combining different approaches, we determine that Trim69 drives the accumulation of stable microtubules which we determine to be a common cellular response to type IFNs stimulation. Overall, our study identifies a novel player in the host pathogen relationship that takes place at the cytoskeleton and contribute to shed new light on the behavior of the cytoskeleton during interferon responses. These findings may have large implications in virology but also in cell biology in conditions in which interferon responses are abnormally elevated as is the case of cancer, chronic infections or interferonopathies.