Pegylated Interferon Alfa-2a Monotherapy Results in Suppression of HIV Type 1 Replication and Decreased Cell-Associated HIV DNA Integration

HIV-1 Immunopathogenesis Laboratory, The Wistar Institute, Philadelphia, USA.
The Journal of Infectious Diseases (Impact Factor: 6). 10/2012; 207(2). DOI: 10.1093/infdis/jis663
Source: PubMed


Background. Antiretroviral therapy (ART)-mediated immune reconstitution fails to restore the capacity of the immune system to spontaneously control HIV replication.Methods. 23 HIV-1 infected, virologically-suppressed subjects on ART (CD4 >450 cells/ml) were randomized to add Peg-IFN-α2A 180 (arm A) or 90 (arm B) μg/week to current ART. After 5 weeks, ART was interrupted and Peg-IFN-α2A continued for up to 12 weeks (primary endpoint) with option to continue to 24 weeks. Endpoints included virologic failure (viral load, VL ≥ 400 copies/ml) and adverse events. Residual VL and HIV-1 DNA integration were also assessed.Results. At week 12 of Peg-IFN-α2A monotherapy, viral suppression was observed in 9/20 (45%) subjects, a significantly greater proportion than expected (arm A p=0.0088; arm B p=0.0010; combined arms p<0.0001). Over 24 weeks, both arms had lower proportions of VL rebound than an historical control (arm A, p= 0.0046; arm B, p= 0.0011). Subjects who sustained VL < 400 copies/ml had decreased the levels of integrated HIV DNA (p= 0.0313), but increased residual VL (p=0.0078) when compared to subjects with endpoint failure.Conclusions. Peg-IFN-α2A immunotherapy resulted in control of HIV replication and decreased HIV-1 integration, supporting a role for immune-mediated approaches in HIV suppression and/or eradication.

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Available from: Michael P Busch, Jul 23, 2015
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    • "Several studies have demonstrated that IFN-α treatment potently suppresses HIV-1 viremia in chronically infected individuals [3]–[6]. A provocative recent report demonstrated that IFN-α treatment results in sustained viral suppression in the absence of antiretroviral therapy (ART) and significant reduction in the size of the HIV-1 reservoir in chronically-infected individuals [7], [8]. A related analysis of the effects of IFN-α/ribavirin therapy on the HIV-1 latent reservoir in HIV/HCV-coinfected individuals reported a similar, significant reduction in reservoir size [9]. "
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    ABSTRACT: Background Interferon-α (IFN-α) treatment suppresses HIV-1 viremia and reduces the size of the HIV-1 latent reservoir. Therefore, investigation of the molecular and immunologic effects of IFN-α may provide insights that contribute to the development of novel prophylactic, therapeutic and curative strategies for HIV-1 infection. In this study, we hypothesized that microRNAs (miRNAs) contribute to the IFN-α-mediated suppression of HIV-1. To inform the development of novel miRNA-based antiretroviral strategies, we investigated the effects of exogenous IFN-α treatment on global miRNA expression profile, HIV-1 viremia, and potential regulatory networks between miRNAs and cell-intrinsic anti-HIV-1 host factors in vivo. Methods Global miRNA expression was examined in longitudinal PBMC samples obtained from seven HIV/HCV-coinfected, antiretroviral therapy-naïve individuals before, during, and after pegylated interferon-α/ribavirin therapy (IFN-α/RBV). We implemented novel hybrid computational-empirical approaches to characterize regulatory networks between miRNAs and anti-HIV-1 host restriction factors. Results miR-422a was the only miRNA significantly modulated by IFN-α/RBV in vivo (p<0.0001, paired t test; FDR<0.037). Our interactome mapping revealed extensive regulatory involvement of miR-422a in p53-dependent apoptotic and pyroptotic pathways. Based on sequence homology and inverse expression relationships, 29 unique miRNAs may regulate anti-HIV-1 restriction factor expression in vivo. Conclusions The specific reduction of miR-422a is associated with exogenous IFN-α treatment, and likely contributes to the IFN-α suppression of HIV-1 through the enhancement of anti-HIV-1 restriction factor expression and regulation of genes involved in programmed cell death. Moreover, our regulatory network analysis presents additional candidate miRNAs that may be targeted to enhance anti-HIV-1 restriction factor expression in vivo.
    PLoS ONE 10/2014; 9(10):e109220. DOI:10.1371/journal.pone.0109220 · 3.23 Impact Factor
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    • "Therapeutic administration of pegylated IFN-α2 have rendered potent anti-viral and immune enhancing effects against hepatitis B virus infection (85, 86). A recent clinical trial has shown that similar outcomes could be achieved even when pegylated IFN-α2 is administered to HIV-infected patients (87). Systemic administration of IFN-α and/or IFN-β has also been reported to reduce viral growth and clinical manifestations of herpes zoster, herpes simplex virus, and cytomegalovirus (CMV) infections (88–91). "
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    ABSTRACT: It has been well-established that type I interferons (IFN-Is) have pleiotropic effects and play an early central role in the control of many acute viral infections. However, their pleiotropic effects are not always beneficial to the host and in fact several reports suggest that the induction of IFN-Is exacerbate disease outcomes against some bacterial and chronic viral infections. In this brief review, we probe into this mystery and try to develop answers based on past and recent studies evaluating the roles of IFN-Is in infection and immunity as this is vital for developing effective IFN-Is based therapeutics and vaccines. We also discuss the biological roles of an emerging IFN-I, namely IFN-ε, and discuss its potential use as a mucosal therapeutic and/or vaccine adjuvant. Overall, we anticipate the discussions generated in this review will provide new insights for better exploiting the biological functions of IFN-Is in developing efficacious therapeutics and vaccines in the future.
    Frontiers in Immunology 08/2014; 5:412. DOI:10.3389/fimmu.2014.00412
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    • "Importantly, our study raises the hypothesis that retained innate immune parameters such as pDC frequency may also predict immune control over viral replication on anti-retroviral therapy. In support of this hypothesis, pDC levels in HIV-1 infected subjects during anti-retroviral therapy have been associated with viral control upon anti-retroviral therapy interruption [67], [68] and the addition of IFN-alpha while receiving anti-retroviral therapy has been associated with greater viral control [69], [70], [71]. In addition, we have independently observed that a combination of Gag-specific HIV-specific CD3+/CD4−/perforin+/IFN-gamma+ cells and the frequency of pDC when measured on anti-retroviral therapy predicted viral set-point after anti-retroviral therapy interruption in 31 subjects (unpublished data). "
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    ABSTRACT: HIV-1 infected viremic controllers maintain durable viral suppression below 2000 copies viral RNA/ml without anti-retroviral therapy (ART), and the immunological factor(s) associated with host control in presence of low but detectable viral replication are of considerable interest. Here, we utilized a multivariable analysis to identify which innate and adaptive immune parameters best correlated with viral control utilizing a cohort of viremic controllers (median 704 viral RNA/ml) and non-controllers (median 21,932 viral RNA/ml) that were matched for similar CD4+ T cell counts in the absence of ART. We observed that HIV-1 Gag-specific CD8+ T cell responses were preferentially targeted over Pol-specific responses in viremic controllers (p = 0.0137), while Pol-specific responses were positively associated with viral load (rho = 0.7753, p = 0.0001, n = 23). Viremic controllers exhibited significantly higher NK and plasmacytoid dendritic cells (pDC) frequency as well as retained expression of the NK CD16 receptor and strong target cell-induced NK cell IFN-gamma production compared to non-controllers (p<0.05). Despite differences in innate and adaptive immune function however, both viremic controllers (p<0.05) and non-controller subjects (p<0.001) exhibited significantly increased CD8+ T cell activation and spontaneous NK cell degranulation compared to uninfected donors. Overall, we identified that a combination of innate (pDC frequency) and adaptive (Pol-specific CD8+ T cell responses) immune parameters best predicted viral load (R2 = 0.5864, p = 0.0021, n = 17) by a multivariable analysis. Together, this data indicates that preferential Gag-specific over Pol-specific CD8+ T cell responses along with a retention of functional innate subsets best predict host control over viral replication in HIV-1 infected viremic controllers compared to chronically-infected non-controllers.
    PLoS ONE 07/2014; 9(7):e103209. DOI:10.1371/journal.pone.0103209 · 3.23 Impact Factor
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