Characteristics of IFITM, the newly identified IFN-inducible anti-HIV-1 family proteins

Chutiwitoonchai, Nopporn; Hiyoshi, Masateru; Hiyoshi-Yoshidomi, Yuka; Hashimoto, Michihiro; Tokunaga, Kenzo; Suzu, Shinya

doi:10.1016/j.micinf.2012.12.003

Cited by 52 publications

(65 citation statements)

References 42 publications

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“…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). The NL4-3 strain of HIV has been reported to be resistant to inhibition by full-length but not C-terminally truncated IFITM1, potentially due to differential cellular localization of the two IFITM1 protein species (64).…”

Section: Discussionmentioning

confidence: 99%

Cytokines Elevated in HIV Elite Controllers Reduce HIV ReplicationIn Vitroand 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 ReplicationIn Vitroand Modulate HIV Restriction Factor Expression

Jacobs

Keating

Abdel‐Mohsen

et al. 2017

J Virol

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“…To interpret the functional impact of the changes observed it is important to keep in mind that: IFIT1 and IFIT3 are both implicated to function against viral infections (19); OASL functions in antiviral response (20); AZU1 serves as an important mediator during the initiation of the immune response (30); and APOBEC3G promotes cytidine deaminase-dependent DNA repair to render radiation resistance in lymphoma (48). In addition, IFN-inducible IFITM proteins (IFITM1, 2 and 3) inhibit the replication of various viruses including HIV-1 (21). Therefore, functions of the single-dose treatment gene signature support the fact that few genes are implicated in eliciting an immune response that could possibly be exploited with immunotherapy or vaccination to harness the tumor cell mediated immunogenic events.…”

Section: Discussionmentioning

confidence: 99%

Defining Molecular Signature of Pro-Immunogenic Radiotherapy Targets in Human Prostate Cancer Cells

et al. 2014

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To understand the impact of clinically relevant radiation therapy (RT) on tumor immune gene expression and to utilize the changes that occur during treatment to improve cancer treatment outcome, we examined how immune response genes are modulated in prostate cancer cells of varying p53 status. LNCaP (p53 wild-type), PC3 (p53 null) and DU145 (p53 mutant) cells received a 10 Gy single dose or 1 Gy × 10 multifractionated radiation dose to simulate hypofractionated and conventionally fractionated prostate radiotherapy. Total RNA was isolated 24 h after multi-fractionated radiation treatment and single-dose treatments and subjected to microarray analysis and later validated by RT-PCR. RT-PCR was utilized to identify total-dose inflection points for significantly upregulated genes in response to multifractionated radiation therapy. Radiation-induced damage-associated molecular pattern molecules (DAMPs) and cytokine analyses were performed using bioluminescence and ELISA. Multifractionated doses activated immune response genes more robustly than single-dose treatment, with a relatively larger number of immune genes upregulated in PC3 compared to DU145 and LNCaP cells. The inflection point of multifractionated radiation-induced immune genes in PC3 cells was observed in the range of 8–10 Gy total radiation dose. Although both multifractionated and single-dose radiation-induced proinflammatory DAMPs and positively modulated the cytokine environment, the changes were of higher magnitude with multifractionated therapy. The findings of this study together with the gene expression data suggest that cells subjected to multifractionated radiation treatment would promote productive immune cell–tumor cell interactions.

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“…An overexpression screen of interferon-stimulated genes revealed that IFITM3 and perhaps IFITM2 can control HIV-1 [20]. Further in vitro studies using overexpression of IFITM1-3 and depletion of these proteins by RNA interference substantiated the evidence that these proteins are HIV-1 restriction factors [21–23]. Consistent with the notion that IFITM3 restricts RNA virus infection by blocking fusion [24, 25], it is believed that IFITM3 and IFITM2 proteins also inhibit fusion of HIV-1 [21, 22].…”

Section: Restriction Of Hiv-1 At the Membranementioning

confidence: 99%

Mouse knockout models for HIV-1 restriction factors

Rehwinkel

2014

Cell. Mol. Life Sci.

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Infection of cells with human immunodeficiency virus 1 (HIV-1) is controlled by restriction factors, host proteins that counteract a variety of steps in the life cycle of this lentivirus. These include SAMHD1, APOBEC3G and tetherin, which block reverse transcription, hypermutate viral DNA and prevent progeny virus release, respectively. These and other HIV-1 restriction factors are conserved and have clear orthologues in the mouse. This review summarises studies in knockout mice lacking HIV-1 restriction factors. In vivo experiments in such animals have not only validated in vitro data obtained from cultured cells, but have also revealed new findings about the biology of these proteins. Indeed, genetic ablation of HIV-1 restriction factors in the mouse has provided evidence that restriction factors control retroviruses and other viruses in vivo and has led to new insights into the mechanisms by which these proteins counteract infection. For example, in vivo experiments in knockout mice demonstrate that virus control exerted by restriction factors can shape adaptive immune responses. Moreover, the availability of animals lacking restriction factors opens the possibility to study the function of these proteins in other contexts such as autoimmunity and cancer. Further in vivo studies of more recently identified HIV-1 restriction factors in gene targeted mice are, therefore, justified.

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Characteristics of IFITM, the newly identified IFN-inducible anti-HIV-1 family proteins

Cited by 52 publications

References 42 publications

Cytokines Elevated in HIV Elite Controllers Reduce HIV ReplicationIn Vitroand Modulate HIV Restriction Factor Expression

Cytokines Elevated in HIV Elite Controllers Reduce HIV ReplicationIn Vitroand Modulate HIV Restriction Factor Expression

Defining Molecular Signature of Pro-Immunogenic Radiotherapy Targets in Human Prostate Cancer Cells

Mouse knockout models for HIV-1 restriction factors

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