Interferon (IFN) plays a central role in host intrinsic immunity to viral infection, the underlying mechanism of which remains poorly defined. Towards this goal, we have recently shown that interferon-induced transmembrane (IFITM) proteins profoundly inhibit the membrane fusion and infection of a number of enveloped viruses, including HIV-1. Interestingly, we found that, while human IFITM2 and IFITM3 impede HIV- 1 (BH10) entry, human IFITM1 impairs viral infectivity. Notably, the prolonged culture of BH10 HIV-1 led to the emergence of mutations in HIV-1 Env that render the virus resistant to IFITM1 inhibition, suggesting that IFITMs may functionally act on HIV-1 Env and diminish viral infectivity. The goal of this R01 project is to determine the mechanisms by which IFITM proteins inhibit distinct steps of HIV replication, as well as viral antagonisms.
Aim 1 will address how IFITM proteins inhibit HIV-1 entry. We will use novel cell-cell fusion and single virus fusion techniques to test the hypothesis that both hemifusion and pore expansion are inhibited by IFITM2 and IFITM3.
Aim 2 will focus on how IFITM proteins, especially IFITM1, diminish HIV-1 infectivity. We will test the central hypothesis that IFITM proteins are incorporated into HIV-1 particles and functionally inactivate HIV-1 Env activity.
Aim 3 will characterize HIV-1 antagonisms against IFITMs, particularly the possible role of HIV-1 Env in this process. Collectively, results from this project will provide critical insights into the mechanisms of actio of IFITMs, and will aid in the development of novel antiviral agents against HIV-1 infection.

Public Health Relevance

Viruses must enter host cells to initiate infection, and hosts have evolved various strategies to limit viral infections. We study how some cellular factors intrinsically block the viral entry and infections, including those of pathogenic HIV-1. The proposed studies may lead to novel strategies against viral diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI112381-01
Application #
8730947
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Sharma, Opendra K
Project Start
2014-02-05
Project End
2019-01-31
Budget Start
2014-02-05
Budget End
2015-01-31
Support Year
1
Fiscal Year
2014
Total Cost
$319,137
Indirect Cost
$104,712
Name
University of Missouri-Columbia
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
Yu, Jingyou; Liang, Chen; Liu, Shan-Lu (2017) Interferon-inducible LY6E Protein Promotes HIV-1 Infection. J Biol Chem 292:4674-4685
Kodigepalli, Karthik M; Li, Minghua; Liu, Shan-Lu et al. (2017) Exogenous expression of SAMHD1 inhibits proliferation and induces apoptosis in cutaneous T-cell lymphoma-derived HuT78 cells. Cell Cycle 16:179-188
Cui, Beibei; Liu, Wenli; Wang, Xiaoya et al. (2017) Brucella Omp25 Upregulates miR-155, miR-21-5p, and miR-23b to Inhibit Interleukin-12 Production via Modulation of Programmed Death-1 Signaling in Human Monocyte/Macrophages. Front Immunol 8:708
Miller, A Dusty; De Las Heras, Marcelo; Yu, Jingyou et al. (2017) Evidence against a role for jaagsiekte sheep retrovirus in human lung cancer. Retrovirology 14:3
Wang, Yimeng; Pan, Qinghua; Ding, Shilei et al. (2017) The V3 Loop of HIV-1 Env Determines Viral Susceptibility to IFITM3 Impairment of Viral Infectivity. J Virol 91:
Wilkins, Jordan; Zheng, Yi-Min; Yu, Jingyou et al. (2016) Nonhuman Primate IFITM Proteins Are Potent Inhibitors of HIV and SIV. PLoS One 11:e0156739
Markosyan, Ruben M; Miao, Chunhui; Zheng, Yi-Min et al. (2016) Induction of Cell-Cell Fusion by Ebola Virus Glycoprotein: Low pH Is Not a Trigger. PLoS Pathog 12:e1005373
Qian, Jin; Le Duff, Yann; Wang, Yimeng et al. (2015) Primate lentiviruses are differentially inhibited by interferon-induced transmembrane proteins. Virology 474:10-8
Jia, Rui; Ding, Shilei; Pan, Qinghua et al. (2015) The C-terminal sequence of IFITM1 regulates its anti-HIV-1 activity. PLoS One 10:e0118794
Yu, Jingyou; Li, Minghua; Wilkins, Jordan et al. (2015) IFITM Proteins Restrict HIV-1 Infection by Antagonizing the Envelope Glycoprotein. Cell Rep 13:145-156

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