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Human myxovirus resistance 2 (MX2) can restrict HIV-1 and herpesviruses at a post-entry step through a process requiring an interaction between MX2 and the viral capsids. The involvement of other host cell factors, however, remains poorly understood. Here, we mapped the proximity interactome of MX2, revealing strong enrichment of phenylalanine-glycine (FG)-rich proteins related to the nuclear pore complex as well as proteins that are part of cytoplasmic ribonucleoprotein granules. MX2 interacted with these proteins to form multiprotein cytoplasmic biomolecular condensates that were essential for its anti-HIV-1 and anti-herpes simplex virus 1 (HSV-1) activity. MX2 condensate formation required the disordered N-terminal region and MX2 dimerization. Incoming HIV-1 and HSV-1 capsids associated with MX2 at these dynamic cytoplasmic biomolecular condensates, preventing nuclear entry of their viral genomes. Thus, MX2 forms cytoplasmic condensates that likely act as nuclear pore decoys, trapping capsids and inducing premature viral genome release to interfere with nuclear targeting of HIV-1 and HSV-1. [Display omitted] • Interferon-induced antiviral protein MX2 forms cytoplasmic condensates with FG Nups • MX2's N-terminal domain and dimerization are required for condensate formation • Restriction of HIV-1 and HSV-1 by MX2 requires condensate formation • MX2 condensates trap HIV-1 capsids and cause premature release of HSV-1 genomes MX2 restricts HIV-1 and herpes simplex virus 1 (HSV-1) through a poorly understood mechanism. Moschonas et al. reveal that MX2 assembles FG nucleoporins into cytoplasmic biomolecular condensates that interact with incoming capsids to trap them or induce premature viral genome release. MX2's N-terminal domain controls condensate formation, which is essential for HIV-1 and HSV-1 restriction. [ABSTRACT FROM AUTHOR]

To complete their replication cycle, retroviruses need to integrate a DNA copy of their RNA genome into a host chromosome. Integration site selection is not random and is driven by multiple viral and cellular host factors specific to different classes of retroviruses. Today, overwhelming evidence from cell culture, animal experiments and clinical data suggests that integration sites are important for retroviral replication, oncogenesis and/or latency. In this review, we will summarize the increasing knowledge of the mechanisms underlying the integration site selection of the gammaretrovirus MLV and the lentivirus HIV-1. We will discuss how host factors of the integration site selection of retroviruses may steer the development of safer viral vectors for gene therapy. Next, we will discuss how altering the integration site preference of HIV-1 using small molecules could lead to a cure for HIV-1 infection. [ABSTRACT FROM AUTHOR]