RNA-associated Early-stage Anti-viral Factor (REAF) is a major component of LV2 restriction.
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HIV and SIV replication in human cells is restricted at early post-entry steps by host inhibitory factors. We previously described and characterised an early phase restriction of HIV-1 and 2 replication in human cell lines, primary macrophages and PBMCs. The restriction was termed Lentiviral restriction 2 (Lv2). The viral determinants of Lv2 susceptibility mapped to the HIV-2 Env and CA. We subsequently reported a whole genome siRNA screen for factors involved in to HIV which identified RNA-associated Early-stage Anti-viral Factor (REAF). Using HIV-2 chimeras of susceptible and non-susceptible viruses we show here that REAF is a major component of the previously described Lv2. Further studies of the viral CA demonstrate that the CA mutation I73V (previously called I207V), a potent determinant for HIV-2, is a weak determinant of susceptibility for HIV-1. More potent CA determinants for HIV-1 REAF restriction were identified at P38A, N74D, G89V and G94D. These results firmly establish that in HIV-1 CA is a strong determinant of susceptibility to LV2/REAF. Similar to HIV-2 the HIV-1 Env can rescue sensitive CAs from restriction. We conclude that REAF is a major component of the previously described Lv2 restriction.Importance Measures taken by the host cell to combat infection drive the evolution of pathogens to counteract or side step them. The study of such virus-host conflicts can point to possible weaknesses in the arsenal of viruses and may lead to the rational design of anti-viral agents. Here we describe our discovery that the host restriction factor REAF fulfils the same criteria previously used to describe Lentiviral restriction (Lv2). We show that, like HIV-1 CA, the CA of HIV-1 is a strong determinant of LV2/REAF susceptibility. We illustrate how HIV counteracts LV2/REAF by using an envelope with alternative routes of entry into cells.
AuthorsMarno, KM; O'Sullivan, E; Jones, CE; Díaz-Delfín, J; Pardieu, C; Sloan, RD; McKnight, Á
- Immune Systems