IFITM Proteins Incorporated into HIV-1 Virions Impair Viral Fusion and Spread

Compton, Alex A.; Bruel, Timothée; Porrot, Françoise; Mallet, Adeline; Sachse, Martin; Euvrard, Marine; Liang, Chen; Casartelli, Nicoletta; Schwartz, Olivier

doi:10.1016/j.chom.2014.11.001

Cited by 182 publications

(263 citation statements)

References 53 publications

(81 reference statements)

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“…IFITM2, but not IFITM1, impedes HIV entry into cells, and neither protein affects cell proliferation or CD4 cell surface expression though the intracellular moiety of IFITM1 is required for anti-HIV activity (60). More recently it has been shown that IFITMs, particularly IFITM2 and IFITM3, colocalize with Env and Gag proteins and can be incorporated into nascent virions, which can impair fusion to target cells (61,62). IFITMs have relatively modest HIV-suppressive activity, and it is hypothesized that these proteins act in part by interfering with viral protein production (63).…”

Section: Discussionmentioning

confidence: 99%

Cytokines Elevated in HIV Elite Controllers Reduce HIV Replication In Vitro and Modulate HIV Restriction Factor Expression

Jacobs

Keating

Abdel‐Mohsen

et al. 2017

J Virol

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A subset of HIV-infected individuals termed elite controllers (ECs) maintain CD4 ϩ T cell counts and control viral replication in the absence of antiretroviral therapy (ART). Systemic cytokine responses may differentiate ECs from subjects with uncontrolled viral replication or from those who require ART to suppress viral replication. We measured 87 cytokines in four groups of women: 73 ECs, 42 with pharmacologically suppressed viremia (ART), 42 with uncontrolled viral replication (noncontrollers [NCs]), and 48 HIV-uninfected (NEG) subjects. Four cytokines were elevated in ECs but not NCs or ART subjects: CCL14, CCL21, CCL27, and XCL1. In addition, median stromal cell-derived factor-1 (SDF-1) levels were 43% higher in ECs than in NCs. The combination of the five cytokines suppressed R5 and X4 virus replication in resting CD4 ϩ T cells, and individually SDF-1␤, CCL14, and CCL27 suppressed R5 virus replication, while SDF-1␤, CCL21, and CCL14 suppressed X4 virus replication. Functional studies revealed that the combination of the five cytokines upregulated CD69 and CCR5 and downregulated CXCR4 and CCR7 on CD4 ϩ T cells. The CD69 and CXCR4 effects were driven by SDF-1, while CCL21 downregulated CCR7. The combination of the EC-associated cytokines induced expression of the anti-HIV host restriction factors IFITM1 and IFITM2 and suppressed expression of RNase L and SAMHD1. These results identify a set of cytokines that are elevated in ECs and define their effects on cellular activation, HIV coreceptor expression, and innate restriction factor expression. This cytokine pattern may be a signature characteristic of HIV-1 elite control, potentially important for HIV therapeutic and curative strategies.IMPORTANCE Approximately 1% of people infected with HIV control virus replication without taking antiviral medications. These subjects, termed elite controllers (ECs), are known to have stronger immune responses targeting HIV than the typical HIV-infected subject, but the exact mechanisms of how their immune responses control infection are not known. In this study, we identified five soluble immune signaling molecules (cytokines) in the blood that were higher in ECs than in subjects with typical chronic HIV infection. We demonstrated that these cytokines can activate CD4 ϩ T cells, the target cells for HIV infection. Furthermore, these five EC-

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Section: Discussionmentioning

confidence: 99%

Cytokines Elevated in HIV Elite Controllers Reduce HIV Replication In Vitro and Modulate HIV Restriction Factor Expression

Jacobs

Keating

Abdel‐Mohsen

et al. 2017

J Virol

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“…As a subunit of PBAF, ARID2 was also found to regulate the expression of interferon induced transmembrane protein 1 (IFITM1) [16]. IFITM1 is an IFN-induced antiviral protein which prevent multiple virus entry, including SARS coronavirus (SARS-CoV), Ebola virus (EBOV), Dengue virus (DNV), human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) [26][27][28][29][30]. IFITM1 was also found to regulate cancer cell proliferation and invasion.…”

Section: Discussionmentioning

confidence: 99%

miR-208-3p promotes hepatocellular carcinoma cell proliferation and invasion through regulating ARID2 expression

Peng

You

et al. 2015

Experimental Cell Research

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MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression at post-transcriptional level. miRNA dysregulation plays a causal role in cancer progression. In this study, miR-208-3p was highly expressed and directly repressed ARID2 expression. As a result, ARID2 expression in hepatocellular carcinoma (HCC) was decreased. In vitro, miR-208-3p down-regulation and ARID2 over-expression elicited similar inhibitory effects on HCC cell proliferation and invasion. In vivo test results revealed that miR-208-3p down-regulation inhibited HCC tumorigenesis in Hep3B cells. Moreover, ARID2 was possibly a downstream element of transforming growth factor beta1 (TGFβ1)/miR-208-3p/ARID2 regulatory pathway. These findings suggested that miR-208-3p up-regulation is associated with HCC cell progression and may provide a new target for liver cancer treatment.

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“…Initial characterizations showed that IFITM proteins do not interfere with HIV-1 infection (1,11). Subsequent studies demonstrated that IFITM1 or IFITM3 can suppress entry and replication of HIV-1 (12)(13)(14). The role of cellular and virion-associated IFITM3 in inhibiting cell-to-cell transmission of CXCR4 (X4)-tropic viruses and infection of HIV-1 in new target cells has also been described (13).…”

mentioning

confidence: 99%

Δ20 IFITM2 differentially restricts X4 and R5 HIV-1

Grotefend

Tsai

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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CCR5 (R5)-tropic, but not CXCR4 (X4)-tropic, HIV-1 is associated with primary HIV-1 infection and transmission. Recent studies have shown that IFN-induced transmembrane (IFITM) proteins, including IFITM1, IFITM2, and IFITM3, restrict a broad range of viruses. Here, we demonstrate that an IFITM2 isoform (Δ20 IFITM2) lacking 20 amino acids at the N terminus differentially restricts X4 and R5 HIV-1. Δ20 IFITM2 suppresses replication of X4 HIV-1 strains by inhibiting their entry. High levels of Δ20 IFITM2 expression could be detected in CD4 T cells and in monocytes. Infection of X4 viruses in monocyte-derived macrophages and dendritic cells is enhanced upon depletion of IFITM2 isoforms. Furthermore, we also show that coreceptor use is the determining factor for differential HIV-1 restriction of Δ20 IFITM2. When we replace the C terminus of CCR5 with the C terminus of CXCR4, R5 viruses become more susceptible to Δ20 IFITM2-mediated restriction. In contrast to previous studies, our research reveals that neither X4 nor R5 HIV-1 is suppressed by IFITM2 and IFITM3. The multifactor gatekeeping model has been proposed to explain restriction of X4 viruses in the early stage of HIV-1 diseases. Our findings indicate that Δ20 IFITM2 may serve as a major contributor to this gatekeeping mechanism.

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IFITM Proteins Incorporated into HIV-1 Virions Impair Viral Fusion and Spread

Cited by 182 publications

References 53 publications

Cytokines Elevated in HIV Elite Controllers Reduce HIV Replication In Vitro and Modulate HIV Restriction Factor Expression

Cytokines Elevated in HIV Elite Controllers Reduce HIV Replication In Vitro and Modulate HIV Restriction Factor Expression

miR-208-3p promotes hepatocellular carcinoma cell proliferation and invasion through regulating ARID2 expression

Δ20 IFITM2 differentially restricts X4 and R5 HIV-1

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