SERINC incorporation into HIV-1 particles appears to affect the conformation of the envelope glycoprotein (Env) as measured by increased exposure of sequestered epitopes, and it interferes with membrane fusion by impeding Env clustering, intermediates in the fusion pathway 7, lipid ordering 8, and expansion of the fusion pore 9, 10, 11, 12. SERINCs may have multiple functions that collectively interfere with virus entry. Our results demonstrate that SERINCs are membrane transporters that flip lipids, resulting in a loss of membrane asymmetry that is strongly correlated with changes in Env conformation and loss of infectivity. SERINC effects in HIV-1 and MLV are counteracted by Nef and GlycoGag, respectively. Furthermore, SERINC3, SERINC5 and the scramblase TMEM16F expose PS on the surface of HIV-1 and reduce infectivity, with similar results in MLV.

Consistently, purified hSERINCs reconstituted into proteoliposomes induce flipping of phosphatidylserine (PS), phosphatidylethanolamine and phosphatidylcholine. The design resembles non-ATP-dependent lipid transporters.

Here, we determine cryoEM maps of full-length human SERINC3 and an ICL4 deletion construct, which reveal that hSERINC3 is comprised of two α-helical bundles connected by a ~ 40-residue, highly tilted, “crossmember” helix.

The HIV-1 accessory protein Nef abrogates incorporation of SERINCs via binding to intracellular loop 4 (ICL4). The host proteins SERINC3 and SERINC5 are HIV-1 restriction factors that reduce infectivity when incorporated into the viral envelope.

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