S2 from Equine infectious anemia virus is an infectivity factor which counteracts the retroviral inhibitors SERINC5 and SERINC3

Abstract

The lentivirus equine infectious anemia virus (EIAV) encodes the small protein S2, a pathogenic determinant that is important for virus replication and disease progression in horses. No molecular function had been linked to this accessory protein. We report that S2 can replace the activity of Negative factor (Nef) in HIV-1 infectivity, being required to antagonize the inhibitory activity of Serine incorporator (SERINC) proteins on Nef-defective HIV-1. Like Nef, S2 excludes SERINC5 from virus particles and requires an ExxxLL motif predicted to recruit the clathrin adaptor, Adaptor protein 2 (AP2). Accordingly, functional endocytic machinery is essential for S2-mediated infectivity enhancement, and S2-mediated enhancement is impaired by inhibitors of clathrin-mediated endocytosis. In addition to retargeting SERINC5 to a late endosomal compartment, S2 promotes host factor degradation. Emphasizing the similarity with Nef, we show that S2 is myristoylated, and, as is compatible with a crucial role in posttranslational modification, its N-terminal glycine is required for anti-SERINC5 activity. EIAV-derived vectors devoid of S2 are less susceptible than HIV-1 to the inhibitory effect of both human and equine SERINC5. We then identified the envelope glycoprotein of EIAV as a determinant that also modulates retroviral susceptibility to SERINC5, indicating that EIAV has a bimodal ability to counteract the host factor. S2 shares no sequence homology with other retroviral factors known to counteract SERINC5. Like the primate lentivirus Nef and the gammaretrovirus glycoGag, the accessory protein from EIAV is an example of a retroviral virulence determinant that independently evolved SERINC5-antagonizing activity. SERINC5 therefore plays a critical role in the interaction of the host with diverse retrovirus pathogens.retrovirus | restriction factor | virus infection

Antiviral Role of Serine Incorporator 5 (SERINC5) Proteins in Classical Swine Fever Virus Infection

“…However, viruses have evolved various mechanisms to counteract the host antiviral factors (Malim and Emerman, 2008;Sauter and Kirchhoff, 2018). SERINC5 is a novel host restriction factor that defends against viral infections, including that of murine leukemia virus (MLV), human immune deficiency virus (HIV) and equine infectious anemia virus (EIAV) (Ahi et al, 2016;Chande et al, 2016;Trautz et al, 2016). A series of studies have been conducted to elucidate the potential role of SERINC5 as an antiviral effector (Oliver, 2015).…”

“…In addition, other studies have indicated that viral infections also influence restriction factors as well. For instance, the sensitivity of the virus particle to SERINC5 was altered by mutations in the viral envelope glycoprotein (Usami et al, 2015;Ziglio et al, 2015;Ahi et al, 2016;Chande et al, 2016;Beitari et al, 2017). It has also been reported that the viral proteins antagonize SERINC5 by altering its subcellular localization and preventing its insertion into viral particles (Chande et al, 2016).…”

“…For instance, the sensitivity of the virus particle to SERINC5 was altered by mutations in the viral envelope glycoprotein (Usami et al, 2015;Ziglio et al, 2015;Ahi et al, 2016;Chande et al, 2016;Beitari et al, 2017). It has also been reported that the viral proteins antagonize SERINC5 by altering its subcellular localization and preventing its insertion into viral particles (Chande et al, 2016). In the present study, it was observed that SERINC5 expression was reduced by CSFV infection both in vitro and in vivo (Figures 3, 4), which supports the hypothesis that SERINC5 may play a key role in the host defense against CSFV infection.…”

HIV-1 Nef Antagonizes SERINC5 Restriction by Downregulation of SERINC5 via the Endosome/Lysosome System

“…The Nef antagonism plays an important role in the prevalence of primate lentiviruses in their hosts (19). In addition, Ser5 is counteracted by the MLV nonstructural protein glycoGag (14,15) and the EIAV accessory protein S2 (20,21). Thus, Ser5 is a critical host restriction factor for retroviruses.…”

Proteasomal degradation of human SERINC4: a potent host anti-HIV-1 factor that is antagonized by Nef

“…Compared to Ser5, the Ser3 antiviral activity is very weak. The Ser5 antiviral activity is antagonized by HIV-1 Nef (Rosa et al, 2015;Usami et al, 2015), murine leukemia virus (MLV) glycosylated Gag (glycoGag) (Rosa et al, 2015;Usami et al, 2015), and equine infectious anemia virus (EIAV) S2 proteins (Ahi et al, 2016;Chande et al, 2016). We reported that Nef, glycoGag, and S2 proteins downregulate Ser5 from plasma membrane and target Ser5 to endosomes and lysosomes for degradation (Ahmad et al, 2019;Li et al, 2019;Shi et al, 2018).…”