The accessory HIV-1 protein Nef is a major pathogenicity determinant that is crucial for high virus loads and for progression to AIDS. Nef increases the specific infectivity of HIV-1 virions, but the mechanism has long remained enigmatic. We have recently identified the multipass transmembrane proteins SERINC3 and SERINC5 as novel anti-viral factors whose down- regulation by Nef accounts for its effect on HIV-1 infectivity. SERINC5 in particular strongly inhibits the infectivity of Nef-deficient HIV-1 progeny virions. HIV-1 Nef induces the removal of SERINC3 and SERINC5 from the surface of virus-producing cells, which prevents their incorporation into HIV-1 virions and consequently counteracts their inhibitory effects on HIV-1 infectivity. However, it remains unclear how SERINCs affect HIV-1 virions. We propose to investigate what determines the susceptibility of HIV-1 envelope glycoproteins to SERINCs, whether SERINCs account for the ability of Nef to protect a membrane-proximal region of gp41, and whether SERINCs affect the viral lipid envelope. It also remains unclear what step during the early phase of HIV-1 replication is inhibited by virion-associated SERINCs. We propose to investigate the hypothesis that SERINCs inhibit the translocation of the mature viral core into target cells. Finally, we propose to investigate what step of SERINC trafficking is affected by Nef, and what determines the ability of Nef to selectively downregulate those SERINC family members that inhibit HIV-1. These studies are significant, because SERINC3 and SERINC5 are highly expressed in primary HIV-1 target cells. Inhibiting their downregulation by Nef is thus a potential strategy to combat HIV/AIDS.

Public Health Relevance

SERINC3 and SERINC5 are novel anti-viral host proteins that inhibit HIV-1 infectivity and are counteracted by the accessory HIV-1 protein Nef. Our application proposes an in-depth investigation of how SERINCs affect HIV-1 virus particles, and how Nef downregulates them to prevent their uptake into HIV-1 particles. The proposed studies are relevant to public health, because inhibiting the downregulation of SERINCs by Nef is a potential strategy to combat HIV/AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI127263-02
Application #
9295964
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Kuo, Lillian S
Project Start
2016-06-13
Project End
2021-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
2
Fiscal Year
2017
Total Cost
$414,911
Indirect Cost
$147,155
Name
University of Massachusetts Medical School Worcester
Department
Biology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Dai, Weiwei; Usami, Yoshiko; Wu, Yuanfei et al. (2018) A Long Cytoplasmic Loop Governs the Sensitivity of the Anti-viral Host Protein SERINC5 to HIV-1 Nef. Cell Rep 22:869-875