Abstract
The host proteins, SERINC3 and SERINC5, have been recently shown to incorporate into HIV-1 particles and compromise their ability to fuse with target cells, an effect that is antagonized by the viral Nef protein. Envelope (Env) glycoproteins from different HIV-1 isolates exhibit a broad range of sensitivity to SERINC-mediated restriction, and the mechanism by which SERINCs interfere with HIV-1 fusion remains unclear. Here, we show that incorporation of SERINC5 into virions in the absence of Nef inhibits the formation of small fusion pores between viruses and cells. Strikingly, we found that SERINC5 promotes spontaneous functional inactivation of sensitive but not resistant Env glycoproteins. Although SERINC5-Env interaction was not detected by co-immunoprecipitation, incorporation of this protein enhanced the exposure of the conserved gp41 domains and sensitized the virus to neutralizing antibodies and gp41-derived inhibitory peptides. These results imply that SERINC5 restricts HIV-1 fusion at a step prior to small pore formation by selectively inactivating sensitive Env glycoproteins, likely through altering their conformation. The increased HIV-1 sensitivity to anti-gp41 antibodies and peptides suggests that SER5 also delays refolding of the remaining fusion-competent Env trimers.
Highlights
The host proteins, SERINC3 and SERINC5, have been recently shown to incorporate into HIV-1 particles and compromise their ability to fuse with target cells, an effect that is antagonized by the viral Nef protein
Whereas murine leukemia virus (MLV) infection is antagonized by SER5, fusion of HIV-1 particles pseudotyped with vesicular stomatitis virus (VSV)-G or Ebola virus glycoproteins is relatively resistant to this factor [10, 11, 14]
In agreement with the previous reports [10, 11], SER5 incorporation had a more pronounced effect on fusion of particles pseudotyped with HXB2 Env (HXB2pp) than those pseudotyped with JRFL Env
Summary
To assess the effect of SER5 on HIV-cell fusion, we compared the fusion activity of pseudoviruses that contained or lacked SER5 in their membrane or contained the inactive SER2 variant as a control. SER5 inhibited fusion mediated by other HIV-1 clade B and clade A Env glycoproteins to a varied degree (supplemental Fig. S3, A–C), and the inhibitory effect appeared to be largely independent of the target cells (supplemental Fig. S3, D and E). For the same ratio of SER5/Env plasmids used to obtain HXB2 pseudoviruses, virus-cell fusion and FFWO were inhibited to a comparable extent (Fig. 1, D and E). BafA1 only marginally (albeit significantly) increased the fusion efficiency of SER5ϩ HXB2pp compared with untreated control or to viruses lacking SER5 (Fig. 2D). This result argues against excessive virus degradation as the basis for the markedly reduced fusion efficiency of SER5ϩ particles. The above results establish an important link between the inherent stability of Env trimers and sensitivity to SER5, because the resistant fusion proteins appear to be less prone to spontaneous inactivation
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