SERINC5 restricts influenza virus infectivity

Abstract

SERINC5 is a multi-span transmembrane protein that is incorporated into HIV-1 particles in producing cells and inhibits HIV-1 entry. Multiple retroviruses like HIV-1, equine infectious anemia virus and murine leukemia virus are subject to SERINC5 inhibition, while HIV-1 pseudotyped with envelope glycoproteins of vesicular stomatitis virus and Ebola virus are resistant to SERINC5. The antiviral spectrum and the underlying mechanisms of SERINC5 restriction are not completely understood. Here we show that SERINC5 inhibits influenza A virus infection by targeting virus-cell membrane fusion at an early step of infection. Further results show that different influenza hemagglutinin (HA) subtypes exhibit diverse sensitivities to SERINC5 restriction. Analysis of the amino acid sequences of influenza HA1 strains indicates that HA glycosylation sites correlate with the sensitivity of influenza HA to SERINC5, and the inhibitory effect of SERINC5 was lost when certain HA glycosylation sites were mutated. Our study not only expands the antiviral spectrum of SERINC5, but also reveals the role of viral envelope glycosylation in resisting SERINC5 restriction.

SERINC5: One antiviral factor to bind them all

“…We recently found that SERINC5 restricts Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infectivity in the absence of ORF7a, a SARS-CoV-2 accessory protein [ 13 ]. Recent studies reported that SERINC5 inhibits influenza A virus (IAV) infection as well, although, no viral protein was identified to counteract the antiviral effect of SERINC5 [ 14 , 15 ]. Furthermore, hepatitis B virus (HBV) and classical swine flu virus (CSFV) were found to be blocked by SERINC5 [ 16 , 17 ].…”

“…However, it was shown that local changes in viral membrane lipid order following treatment with lipophilic drugs like amphotericin B alleviated SERINC5 restriction on HIV-1 membrane fusion [ 23 ] indicating a possible role of SERINC5 interaction with lipids at the membrane interface. Finally, studies have shown that the route of virus entry (pH dependent versus independent) does not affect SERINC5-mediated restriction of virus entry [ 11 , 14 , 15 , 18 ]. It is worth noting that in the case of IAV, not only virion-associated SERINC5 but also SERINC5 expressed in target cells restricted virion entry, as SERINC5 present in the target cells also inhibited IAV HA-mediated fusion [ 14 ].…”

“…Finally, studies have shown that the route of virus entry (pH dependent versus independent) does not affect SERINC5-mediated restriction of virus entry [ 11 , 14 , 15 , 18 ]. It is worth noting that in the case of IAV, not only virion-associated SERINC5 but also SERINC5 expressed in target cells restricted virion entry, as SERINC5 present in the target cells also inhibited IAV HA-mediated fusion [ 14 ]. Interestingly, the mechanism utilized by SERINC5 to inhibit HBV is distinct from that of retroviruses, SARS-CoV-2, and IAV ( Fig 1 ).…”

“…However, a recent study [ 18 ] indicated that SERINC5 sensitivity of certain envelope glycoproteins is influenced by viral core as well. Similar to HIV-1, IAV strains show differential sensitivity to SERINC5 restriction, which is determined by the N-linked glycosylation pattern of IAV HA [ 14 ]. Interestingly, in the case of SARS-CoV-2, Spike glycoproteins derived from different SARS-CoV-2 variants (Alpha, Beta, Gamma, and Delta) are all sensitive to SERINC5 restriction [ 13 ].…”

“…SERINC5 localizes to the plasma membrane lipid rafts (assembly sites for HIV-1 and IAV) [20] and the endoplasmic reticulum-Golgi intermediate compartment (ERGIC; assembly site for SARS-CoV-2) [13]. In the case of retroviruses, SARS-CoV-2 and IAV, incorporation of SERINC5 in budding virions is needed to block virus-cell membrane fusion (Fig 1) [9,11,[13][14][15]. However, the exact mechanism of SERINC5-mediated inhibition of virion fusion is still not well understood.…”