Viruses | Free Full-Text | Role of Viral Envelope Proteins in Determining Susceptibility of Viruses to IFITM Proteins

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Viruses | Free Full-Text | Role of Viral Envelope Proteins in Determining Susceptibility of Viruses to IFITM Proteins


2.1. Viral Resistance to IFITMs Depends on Envelope Surface Proteins

Early studies suggested that viruses can be either sensitive or resistant to IFITM proteins, and this trait was initially believed to be inherent to each viral species. However, it soon became clear that, at least for some viruses, their sensitivity to IFITMs was strain- or variant-specific [12]. Initial investigations performed on a few laboratory-adapted strains of HIV-1, such as BH1, demonstrated their restriction by IFITMs [24]. Nevertheless, some laboratory-adapted strains like AD8 and primary isolates of HIV-1 that escape the antiviral activity of IFITM proteins were subsequently reported [36,37,38].
Focusing on IFITMs expressed in target cells, the work of Foster et al. revealed that transmitted/founder (T/F) variants of HIV-1, isolated early in infection, exhibited greater resistance to IFITM2 and IFITM3 restriction compared to viral variants isolated during the chronic phase of infection [37]. The observed IFITM phenotypes were transferable to lentiviruses pseudotyped with the respective Env variants, indicating that amino acids changes in the envelope glycoproteins are determinants of IFITM-mediated restriction. When comparing viruses that use different co-receptors (CCR5 or CXCR4), Foster et al. also reported that CCR5-using viruses (R5) tended to be more sensitive to IFITM1 but more resistant to IFITM2/3 than CXCR4-using viruses (X4). This phenotype was attributed to the V3 loop of Env [37]. However, using a large set of HIV-1 strains, including CCR5-, CXCR4- or dual-tropic strains, Yu et al. obtained conflicting results regarding co-receptor usage dependence [39]. More recently, the work of Haider et al. revealed that the cytoplasmic domain of Env is another determinant of susceptibility to IFITM proteins, with its truncation rendering viruses resistant [38].
Similarly, when focusing on the inhibitory activity of IFITMs after incorporation into newly formed viruses, Wang et al. reported that sensitivity to IFITM2/3 is strain-specific [36]. In contrast, virus sensitivity to IFITM1 appears to be consistently low, regardless of the strain. Once again, resistance to IFITM3 action has been attributed to the V3 variable loop of gp120 [36]. More recently, using a broader panel of Env clones originating from laboratory-adapted or primary strains, we confirmed the crucial role played by Env in modulating susceptibility to IFITM3 [35]. By swapping variable domains of Env between sensitive and resistant clones, we demonstrated that both the V3 and V1V2 loops are genetic determinants of resistance to the antiviral activity of IFITM3. However, no link between IFITM3 inhibition of HIV-1 infectivity and HIV-1 coreceptor usage can be observed [35,36]. Using a panel of lentiviruses pseudotyped with Env clones derived from either T/F HIV-1 strains, acute or chronic infections, Beitari et al. also reported that T/F Env clones are relatively resistant to the viral incorporation of IFITM3, but this resistance property diminishes as the infection progresses. This supports the findings by Foster et al. when IFITMs are expressed in target cells [37,40]. One proposed scenario is that adaptive immune pressure and the emergence of neutralizing antibody resistance mutations in HIV-1 Env have led to viral isolates that are more sensitive to IFITM proteins.
Collectively, papers showing the importance of Env in modulating susceptibility of HIV-1 to IFITMs are further supported by the capacity of HIV-1 to overcome IFITM restriction by mutating its env gene during prolonged replication in cell culture [33,41]. Interestingly, while most studies were based on infection of target cells by cell-free HIV-1 particles, the work of Yu et al. carried out in the context of co-culture of HIV-1-infected donor cells with target cells to mimic cell-to-cell HIV transmission, also showed the strain specificity of IFITM inhibition [33].
The susceptibility of hepatitis C virus (HCV) to IFITM proteins has also been reported to be envelope-dependent [42]. Using HCV pseudoparticles (HCVpp)-bearing envelopes (E1E2) from patients with acute infection before seroconversion or patients undergoing liver transplantation due to chronic hepatitis C, Wrench et al. compared envelopes’ susceptibility to the presence of IFITM proteins overexpressed in Huh7.5.1 target cells. Results differed to what was observed for HIV-1. Firstly, the antiviral activity did not significantly differ between IFITM1, IFITM2, and IFITM3 proteins. Secondly, HCV variants isolated pre-seroconversion were more sensitive to IFITM proteins than variants isolated from patients during chronic infection, suggesting that IFITM proteins may exert significant selective pressure on HCV during the acute phase of infection, resulting in viral evasion.
The antiviral pressure exerted by IFITM proteins was also observed for SARS-CoV-2. Following the identification of the first SARS-CoV-2 strain circulating in humans in 2020 (Wuhan-Hu-1), dominant variants of concern (VOCs) with an increasing number of mutations in the spike protein emerged. The initial VOC, Alpha, which became the dominant variant in much of Europe and North America in the first months of 2021, was shown to be more resistant to IFITMs than the parental Wuhan-Hu-1 virus, with resistance to the antiviral protein IFITM2 and enhancement of infection by its paralogue IFITM3 [43]. The increase in resistance can be attributed to one specific mutation in the spike (S) glycoprotein, once again highlighting the importance of surface determinants in modulating the antiviral activity of IFITMs. In contrast to Alpha, the most recent VOC, Omicron, was unique in being sensitive to inhibition by IFITM1, 2, and 3 [44]. Using chimeric spike mutants, the Omicron phenotype’s sensitivity to IFITMs was attributed to the S2 domain of the spike. Omicron emerged later when the population’s humoral immunity was higher. It was the first real neutralizing antibody escape variant, and authors suggested that resistance mutations may have negatively influenced its ability to escape innate immunity, particularly IFITMs’ restriction. This evolution and critical balance between viral evasion of innate and adaptive immunity are similar to what was reported by Foster et al. during the HIV-1 evolution in a host, as mentioned above [37].
While the spike protein appears to modulate the sensitivity of SARS-CoV-2 to IFITM proteins, Kichhoff’s group has shown that experimental design influences the sensitivity of SARS-CoV-2 and other human coronaviruses to IFITM proteins [45,46,47]. Their work suggests that endogenous expression of IFITM2 and/or IFITM3 enhances the replication of both SARS-CoV-1 and SARS-CoV-2, whereas overexpression inhibits them. They also demonstrated that overexpression of IFITM2 and IFITM3 proteins prevents the cell surface expression of ACE2, the entry receptor for SARS-CoV-1 and SARS-CoV-2, thus explaining the inhibitory effect of this artificial overexpression. Furthermore, they showed that the boosting effect of IFITM proteins on viral replication is only observed in the context of native viruses, as pseudoparticles expressing SARS-CoV-1 or SARS-CoV-2 spikes do not reproduce the ability of native viruses to hijack IFITM proteins for efficient infection.

Altogether, these results demonstrate that the antiviral properties of IFITM proteins can be modulated by viral envelope surface glycoproteins. Conversely, beyond just counteracting the antiviral activity of these proteins, some viruses go to the extent of exploiting them for their own benefit to facilitate replication.


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