NEF-independent SERINC5 regulation

The National Institute of Allergy and Infectious Diseases awarded The Research Foundation for the State University of New York $688,030 on July 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate SERINC5 regulation and its role in HIV-1 inhibition.

The research examines mechanisms by which SERINC5, a host antiviral protein that potently inhibits HIV-1 infectivity, is regulated during retrovirus infection. The project investigates a novel nef-independent mechanism of SERINC5 removal from the cell surface using both in vivo and in vitro approaches; explores whether enzymatic activity of host factors and existing drugs can affect SERINC5's anti-HIV-1 effect; and investigates how HIV-1 induces nef-independent mechanisms of SERINC5 inhibition. SERINC5 blocks HIV-1 infectivity by incorporating into nascent virions and preventing virus-cell membrane fusion, but HIV-1's nef protein counteracts this by removing SERINC5 from the plasma membrane. The proposal addresses aspects of HIV-1-mediated SERINC5 inhibition not previously studied.

The Research Foundation for the State University of New York serves as fiscal agent for the State University of New York system. Performance occurs in Buffalo, New York. The award runs from July 1, 2026, through June 30, 2031. This is a Project Grant, the standard assistance type for individual research projects under NIAID's program.

Abstract

Serine incorporator (serinc) family members have emerged as important factors of the host antiviral response that potently inhibit human immunodeficiency virus type 1 (HIV-1) and other retroviruses. Serinc proteins are highly conserved multipass transmembrane proteins that are thought to play important roles in phosphatidylserine and sphingolipid biogenesis. SERINC5, and to a lesser extent SERINC3, block HIV-1 infectivity by becoming incorporated in nascent virions thereby blocking virus-cell membrane fusion during virus entry, in a mechanism that is not very well understood. The focus of this proposal is SERINC5 as IT is the most potent inhibitor of HIV-1 infectivity among all members of the serinc protein family. The important antiviral function of SERINC5 is further evident by the fact that a number of retroviruses encode viral factors that counteract the inhibitory effect of SERINC5. In the case of HIV-1, negative effector (NEF) counteracts SERINC5 by removing IT from the plasma membrane, thereby preventing its incorporation in nascent virions, allowing the produced virions to retain their infectivity. However, over the years a number of questions have emerged about the role of SERINC5 during retrovirus infection. This proposal investigates aspects of HIV-1-mediated inhibition of SERINC5 that have never been previously studied. The first aim examines a novel mechanism by which SERINC5 is removed from the cell surface in a NEF-independent manner, in this aim a two-pronged approach is used by examining SERINC5 regulation both in vivo and in vitro. Moreover, the second aim will explore whether the enzymatic activity of host factors and already existing drugs that target them can affect the anti-HIV-1 effect of SERINC5. The third aim will investigate the mechanism by which HIV-1 can induce NEF-independent mechanisms of SERINC5 inhibition. In summary, these studies utilize a holistic approach to understand the mechanisms utilized by HIV-1 to block the antiretroviral function of SERINC5 in a NEF-independent manner. Due to the potent effect of SERINC5 on HIV-1 infectivity, the findings of this proposal have the potential of providing novel therapeutic strategies and targets that are focused on enhancing the antiretroviral role of SERINC5.