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

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.

Retroviral factors promoting infectivity.

The ability of a virus particle to establish an infectious event is a fundamental property required for viral propagation and survival. Retrovirus invasion of target cells is a multistep process that begins with entry into the cytoplasm and culminates with the integration of the proviral genome into the host DNA. Along this journey, many obstacles await the retrovirus particle and undermine its infectivity. Host-cell barriers to retrovirus infection can either be basic structural components of the eukaryotic cell or specific antiretroviral activities developed by the cell to prevent the retroviral invasion. Resulting from a long host-parasite coevolution, retroviruses have developed auxiliary factors that promote infectivity by conferring the virion the ability to overcome several cellular obstacles, which interfere with the infection process. Here, we provide an overview of different retroviral auxiliary factors that promote virion infectivity, comparing their mechanism of action and highlighting common mechanistic strategies. Special attention is given to infectivity factors that remain enigmatic in the biology of retroviruses.