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Interferon-? Subtypes in an Ex Vivo Model of Acute HIV-1 Infection: Expression, Potency and Effector Mechanisms.

ABSTRACT: HIV-1 is transmitted primarily across mucosal surfaces and rapidly spreads within the intestinal mucosa during acute infection. The type I interferons (IFNs) likely serve as a first line of defense, but the relative expression and antiviral properties of the 12 IFN? subtypes against HIV-1 infection of mucosal tissues remain unknown. Here, we evaluated the expression of all IFN? subtypes in HIV-1-exposed plasmacytoid dendritic cells by next-generation sequencing. We then determined the relative antiviral potency of each IFN? subtype ex vivo using the human intestinal Lamina Propria Aggregate Culture model. IFN? subtype transcripts from the centromeric half of the IFNA gene complex were highly expressed in pDCs following HIV-1 exposure. There was an inverse relationship between IFNA subtype expression and potency. IFN?8, IFN?6 and IFN?14 were the most potent in restricting HIV-1 infection. IFN?2, the clinically-approved subtype, and IFN?1 were both highly expressed but exhibited relatively weak antiviral activity. The relative potencies correlated with binding affinity to the type I IFN receptor and the induction levels of HIV-1 restriction factors Mx2 and Tetherin/BST-2 but not APOBEC3G, F and D. However, despite the lack of APOBEC3 transcriptional induction, the higher relative potency of IFN?8 and IFN?14 correlated with stronger inhibition of virion infectivity, which is linked to deaminase-independent APOBEC3 restriction activity. By contrast, both potent (IFN?8) and weak (IFN?1) subtypes significantly induced HIV-1 GG-to-AG hypermutation. The results unravel non-redundant functions of the IFN? subtypes against HIV-1 infection, with strong implications for HIV-1 mucosal immunity, viral evolution and IFN?-based functional cure strategies.

SUBMITTER: Harper MS

PROVIDER: S-EPMC4631339 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Interferon-α Subtypes in an Ex Vivo Model of Acute HIV-1 Infection: Expression, Potency and Effector Mechanisms.

Harper Michael S MS Guo Kejun K Gibbert Kathrin K Lee Eric J EJ Dillon Stephanie M SM Barrett Bradley S BS McCarter Martin D MD Hasenkrug Kim J KJ Dittmer Ulf U Wilson Cara C CC Santiago Mario L ML

PLoS pathogens 20151103 11

HIV-1 is transmitted primarily across mucosal surfaces and rapidly spreads within the intestinal mucosa during acute infection. The type I interferons (IFNs) likely serve as a first line of defense, but the relative expression and antiviral properties of the 12 IFNα subtypes against HIV-1 infection of mucosal tissues remain unknown. Here, we evaluated the expression of all IFNα subtypes in HIV-1-exposed plasmacytoid dendritic cells by next-generation sequencing. We then determined the relative a ...[more]

PMID: 26529416

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Project description:Although all 12 subtypes of human interferon alpha (IFN-?) bind the same receptor, recent results have demonstrated that they elicit unique host responses and display distinct efficacies in the control of different viral infections. The IFN-?2 subtype is currently in HIV-1 clinical trials, but it has not consistently reduced viral loads in HIV-1 patients and is not the most effective subtype against HIV-1 in vitro We now demonstrate in humanized mice that, when delivered at the same high clinical dose, the human IFN-?14 subtype has very potent anti-HIV-1 activity whereas IFN-?2 does not. In both postexposure prophylaxis and treatment of acute infections, IFN-?14, but not IFN-?2, significantly suppressed HIV-1 replication and proviral loads. Furthermore, HIV-1-induced immune hyperactivation, which is a prognosticator of disease progression, was reduced by IFN-?14 but not IFN-?2. Whereas ineffective IFN-?2 therapy was associated with CD8(+) T cell activation, successful IFN-?14 therapy was associated with increased intrinsic and innate immunity, including significantly higher induction of tetherin and MX2, increased APOBEC3G signature mutations in HIV-1 proviral DNA, and higher frequencies of TRAIL(+) NK cells. These results identify IFN-?14 as a potent new therapeutic that operates via mechanisms distinct from those of antiretroviral drugs. The ability of IFN-?14 to reduce both viremia and proviral loads in vivo suggests that it has strong potential as a component of a cure strategy for HIV-1 infections. The broad implication of these results is that the antiviral efficacy of each individual IFN-? subtype should be evaluated against the specific virus being treated.The naturally occurring antiviral protein IFN-?2 is used to treat hepatitis viruses but has proven rather ineffective against HIV in comparison to triple therapy with the antiretroviral (ARV) drugs. Although ARVs suppress the replication of HIV, they fail to completely clear infections. Since IFN-? acts by different mechanism than ARVs and has been shown to reduce HIV proviral loads, clinical trials are under way to test whether IFN-?2 combined with ARVs might eradicate HIV-1 infections. IFN-? is actually a family of 12 distinct proteins, and each IFN-? subtype has different efficacies toward different viruses. Here, we use mice that contain a human immune system, so they can be infected with HIV. With this model, we demonstrate that while IFN-?2 is only weakly effective against HIV, IFN-?14 is extremely potent. This discovery identifies IFN-?14 as a more powerful IFN-? subtype for use in combination therapy trials aimed toward an HIV cure.

Dataset Information

Interferon-? Subtypes in an Ex Vivo Model of Acute HIV-1 Infection: Expression, Potency and Effector Mechanisms.

Publications

Interferon-α Subtypes in an Ex Vivo Model of Acute HIV-1 Infection: Expression, Potency and Effector Mechanisms.

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