Abstract
SummaryInterferon-induced transmembrane proteins (IFITMs) restrict the entry of diverse enveloped viruses through incompletely understood mechanisms. While IFITMs are reported to inhibit HIV-1, their in vivo relevance is unclear. We show that IFITM sensitivity of HIV-1 strains is determined by the co-receptor usage of the viral envelope glycoproteins as well as IFITM subcellular localization within the target cell. Importantly, we find that transmitted founder HIV-1, which establishes de novo infections, is uniquely resistant to the antiviral activity of IFITMs. However, viral sensitivity to IFITMs, particularly IFITM2 and IFITM3, increases over the first 6 months of infection, primarily as a result of neutralizing antibody escape mutations. Additionally, the ability to evade IFITM restriction contributes to the different interferon sensitivities of transmitted founder and chronic viruses. Together, these data indicate that IFITMs constitute an important barrier to HIV-1 transmission and that escape from adaptive immune responses exposes the virus to antiviral restriction.
Highlights
Robust systemic type 1 interferon (IFN-1) responses are among the earliest host innate immune defenses during acute SIV and HIV-1 infection (Abel et al, 2005; Stacey et al, 2009)
We found that Interferon-induced transmembrane proteins (IFITMs) restriction of HIV-1 is modulated by co-receptor usage and subcellular localization of the IFITM, suggesting different entry pathways depending on Env/receptor interactions
The IFITM expression levels in these engineered cell lines were of a similar magnitude compared to those of monocyte-derived macrophages and CD4+ T cells in the presence and absence of IFN-1 (Figure S1B)
Summary
Robust systemic type 1 interferon (IFN-1) responses are among the earliest host innate immune defenses during acute SIV and HIV-1 infection (Abel et al, 2005; Stacey et al, 2009). While the virus encodes countermeasures against important ISGs, such as APOBEC3G and tetherin (BST2/CD317), other ISGs appear to restrict viral replication in cell culture with no obvious viral evasion mechanism, and their physiological relevance in the transmission and pathogenesis of HIV/AIDS remains unclear (Doyle et al, 2015). One such family of ISGs, the IFN-induced transmembrane proteins 1–3 (IFITMs 1–3), has broad activity against diverse enveloped viruses, influenza A virus (IAV) (reviewed in Smith et al, 2014). A human polymorphism defined by a SNP, rs12252-C, has been proposed to lead to an alternatively spliced variant of IFITM3 that truncates the N terminus after the YxxF motif, thereby reducing its antiviral activity against IAV and accounting for enhanced morbidity in the recent H1N1 swine flu pandemic (Everitt et al, 2012)
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