Distinct effects of treatment with two different interferon-alpha subtypes on HIV-1-associated T-cell activation and dysfunction in humanized mice

Abstract

Objective: Interferon-alpha (IFN-a) has been associated with excessive immune activation and dysfunction during HIV-1 infection. However, evidence suggests specific IFN-a subtypes may be beneficial rather than detrimental. This study compared the effects of treatment with two different IFN-a subtypes on indicators of T-cell activation and dysfunction during HIV-1 infection.Design: Humanized mice were infected with HIV-1 for 5 weeks and then treated with two different IFN-a subtypes for an additional 3 weeks. Splenic T cells were assessed both immediately posttreatment and again 6 weeks after treatment cessation.Methods: HIV-1 infected triple-knockout bone marrow-liver-thymus mice received daily intraperitoneal injections of either IFN-a14 or the clinically approved subtype, IFN-a2. T cells were analysed directly ex vivo for indicators of activation and dysfunction or stimulated to determine their proliferative capacity and ability to produce functional mediators.Results: Unlike IFN-a2, IFN-a14 treatment reduced viremia and resulted in less activated CD4 þ T cells and a lower naı ¨ve to effector CD8 þ T-cell ratio. Despite exhibiting a reduced proliferative response, the frequency of CD8 þ T cells from IFN-a14 treated mice that produced functional mediators and expressed markers of dysfunction was more similar to healthy controls than untreated and IFN-a2 treated mice. Frequencies of exhaustion marker expression remained higher in untreated and IFN-a2 treated mice 6 weeks posttreatment despite similar viral loads between groups at this timepoint.Conclusions: Treatment with different IFN-a subtypes had distinctive effects on T cells during HIV-1 infection. IFN-a14 was associated with fewer indicators of T-cell dysfunction whereas IFN-a2 treatment had little impact.

Distinct Type I Interferon Subtypes Differentially Stimulate T Cell Responses in HIV-1-Infected Individuals

“…In HIV-infected PBMCs the effects of IFN treatment on CD107a + T cells was even stronger compared to HIV-infected LPMCs ( Figure 1F ). In contrast to studies from HIV-infected humanized mice ( 2 , 11 ) in vitro stimulation with IFNα14 and IFNβ significantly increased percentages of CD107a-expressing CD4 + and CD8 + T cells in comparison to untreated and IFNα2-treated HIV-infected PBMCs. Similar effects were also observed in CD56 + NK cells, whereas the changes in CD107a-expressing CD56 + NK cells were not significant in LPMCs and PBMCs ( Figures 1C, F ).…”

“…The experimental data are still puzzling as the different studies showed quite opposing results. We and others have previously shown that during acute and chronic HIV infection of BLThumanized mice, IFNa14 treatment resulted in significantly reduced viremia and the treatment did not induce hyperimmune activation (2,11,12,31). During acute HIV infection treatment with IFNa2 resulted in increased frequencies of CD8 + T cells expressing cytotoxic molecules like CD107a and Granzyme B, and IFNa14 preferentially targeted NK cell responses by increasing TRAIL expression (2).…”

“…During acute HIV infection treatment with IFNα2 resulted in increased frequencies of CD8 + T cells expressing cytotoxic molecules like CD107a and Granzyme B, and IFNα14 preferentially targeted NK cell responses by increasing TRAIL expression ( 2 ). Further, IFNα14 treatment during chronic HIV infection in humanized mice was associated with reduced expression of markers for T cell dysfunction, whereas IFNα2 treatment did not changed the expression rate of exhaustion markers, indicating that exogenous treatment with IFNα2 may not efficiently prevent T cell exhaustion in HIV infection ( 11 ). IFN-blocking experiments in persistently HIV-1 infected humanized mice demonstrated that despite having increased viral loads upon blockade, IFNAR signaling may still drive CD4 + T cell apoptosis and dysfunction of CD4 + and CD8 + T cells during chronic infection ( 25 ).…”

“…Detailed analysis in HIV-infected humanized BLT (bone marrow/liver/thymus) mice in vivo further confirmed this superior antiviral effect of IFNα14, which significantly reduced viral loads and increased expression of HIV restriction factors ( 2 ). Interestingly, IFNα2 treatment increased activation of CD8 + T cells and expression of T cell exhaustion markers ( 2 , 11 ), whereas IFNα14 targeted NK cell effector responses and did not increase the expression of exhaustion markers on CD8 + T cells in HIV-infected humanized mice. Gene therapy with plasmids encoding IFNβ and IFNα14, but not the clinically used IFNα2, confers long-term suppression of HIV-1 replication in HIV-infected humanized mice ( 12 ).…”

Viral and Host Mediators of Non-Suppressible HIV-1 Viremia

“…IFN plays a vital role in the innate host antiviral response and contributes to the suppression of HIV viremia. 60 Compared to ARTsuppressed participants, NSV participants significantly down-regulated transcription of IFN genes and multiple genes involved in the IFN-response pathway (Fig. 4), including key regulators IRF3 and IRF7 (Fig.…”