Abstract
The interferon-inducible transmembrane (IFITM) proteins inhibit a wide range of viruses. We previously reported the inhibition of human immunodeficiency virus type 1 (HIV-1) strain BH10 by human IFITM1, 2 and 3. It is unknown whether other HIV-1 strains are similarly inhibited by IFITMs and whether there exists viral countermeasure to overcome IFITM inhibition. We report here that the HIV-1 NL4-3 strain (HIV-1NL4-3) is not restricted by IFITM1 and its viral envelope glycoprotein is partly responsible for this insensitivity. However, HIV-1NL4-3 is profoundly inhibited by an IFITM1 mutant, known as Δ(117–125), which is deleted of 9 amino acids at the C-terminus. In contrast to the wild type IFITM1, which does not affect HIV-1 entry, the Δ(117–125) mutant diminishes HIV-1NL4-3 entry by 3-fold. This inhibition correlates with the predominant localization of Δ(117–125) to the plasma membrane where HIV-1 entry occurs. In spite of strong conservation of IFITM1 among most species, mouse IFITM1 is 19 amino acids shorter at its C-terminus as compared to human IFITM1 and, like the human IFITM1 mutant Δ(117–125), mouse IFITM1 also inhibits HIV-1 entry. This is the first report illustrating the role of viral envelope protein in overcoming IFITM1 restriction. The results also demonstrate the importance of the C-terminal region of IFITM1 in modulating the antiviral function through controlling protein subcellular localization.
Highlights
Interferon inhibits virus infection by inducing the expression of hundreds of host genes, known as Interferon-stimulated genes (ISGs), some of which encode antiviral effectors [1]
We report that human IFITM1 differentially affects the replication of two closely related human immunodeficiency virus type 1 (HIV-1) strains BH10 and NL4–3 and that the viral envelope glycoprotein is responsible for this differential sensitivity to IFITM1 restriction
We previously showed that IFITM1 mutants lacking this C-terminal sequence still strongly inhibit HIV-1BH10 (Fig. 1B and 1C) [10]
Summary
Interferon inhibits virus infection by inducing the expression of hundreds of host genes, known as Interferon-stimulated genes (ISGs), some of which encode antiviral effectors [1] Among these antiviral proteins are a small protein family called interferon-inducible transmembrane (IFITM) proteins. Subsequent studies revealed that many viruses are susceptible to IFITM restriction These include flaviviruses (West Nile virus, dengue virus, and yellow fever virus), filoviruses (Marburg virus and Ebola virus), SARS coronavirus, reovirus, Rift Valley fever virus, human immunodeficiency virus type 1 (HIV-1), jaagsiekte sheep retrovirus (JSRV), and others [6,7,8,9,10,11,12,13] (reviewed in[14,15]). Single nucleotide polymorphisms in ifitm gene have been shown to associate with pathogenesis severity of influenza A virus infection in humans [16,19]
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