HIV-1 propagation is highly dependent on basal levels of the restriction factor BST2

Sci Adv. 2021 Oct 29;7(44):eabj7398. doi: 10.1126/sciadv.abj7398. Epub 2021 Oct 29.


BST2 is an interferon-inducible antiviral host protein antagonized by HIV-1 Vpu that entraps nascent HIV-1 virions on the cell surface. Unexpectedly, we find that HIV-1 lacking Nef can revert to full replication competence simply by losing the ability to antagonize BST2. Using gene editing together with cell sorting, we demonstrate that even the propagation of wild-type HIV-1 is strikingly dependent on BST2, including in primary human cells. HIV-1 propagation in BST2−/− populations can be fully rescued by exogenous BST2 irrespective of its capacity to signal and even by an artificial BST2-like protein that shares its virion entrapment activity but lacks sequence homology. Counterintuitively, our results reveal that HIV-1 propagation is critically dependent on basal levels of virion tethering by a key component of innate antiviral immunity.