Pegylated Interferon-α2A mono-therapy results in suppression of HIV-1 replication and decreased cell-associated HIV DNA integration.
ABSTRACT 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.
SourceAvailable from: Danushka Kumara Wijesundara[Show abstract] [Hide abstract]
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
[Show abstract] [Hide abstract]
ABSTRACT: Identifying characteristics of the HIV-1 Envelope that are effective in generating broad, protective antibodies remains a hurdle to HIV vaccine design. Emerging evidence of the development of broad and potent neutralizing antibodies in HIV-infected subjects suggests that founder and subsequent progeny viruses may express unique antigenic motifs that contribute to this developmental pathway. We hypothesize that over the course of natural infection, B cells are programmed to develop broad antibodies by exposure to select populations of emerging Envelope quasispecies variants. To test this hypothesis, we identified two unrelated subjects whose antibodies demonstrated increasing breadth against a panel of HIV-1 isolates over time. Full-length functional env genes were cloned longitudinally from these subjects from months after infection through 2.6 to 5.8 years of infection. Motifs associated with the development of breadth in published, cross-sectional studies were found in both subjects. We compared the immunogenicity of Envelope vaccines derived from timepoints obtained during and after broadening of neutralization activity within these subjects. Rabbits were co-immunized four times with selected multiple gp160 DNAs and gp140-trimeric Envelope proteins. Affinity of the polyclonal response increased as a function of boosting. The most rapid and persistent neutralization of multi-clade Tier 1 viruses was elicited by Envelopes that were circulating in plasma at timepoints prior to the development of 50% neutralization breadth in both human subjects. The breadth elicited in rabbits was not improved by exposure to later Envelope variants. These data have implications for vaccine development in describing a target timepoint to identify optimal Envelope immunogens.Journal of Virology 09/2014; 88(22). DOI:10.1128/JVI.01812-14 · 4.65 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: 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.PLoS ONE 10/2014; 9(10):e109220. DOI:10.1371/journal.pone.0109220 · 3.53 Impact Factor