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Port Saint Lucie, FL, United States

Lei Y.,University of North Carolina at Chapel Hill | Lei Y.,University of Pittsburgh | Wen H.,University of North Carolina at Chapel Hill | Yu Y.,University of North Carolina at Chapel Hill | And 14 more authors.
Immunity | Year: 2012

The mitochondrial protein MAVS (also known as IPS-1, VISA, and CARDIF) interacts with RIG-I-like receptors (RLRs) to induce type I interferon (IFN-I). NLRX1 is a mitochondrial nucleotide-binding, leucine-rich repeats (NLR)-containing protein that attenuates MAVS-RLR signaling. Using Nlrx1-/- cells, we confirmed that NLRX1 attenuated IFN-I production, but additionally promoted autophagy during viral infection. This dual function of NLRX1 paralleled the previously described functions of the autophagy-related proteins Atg5-Atg12, but NLRX1 did not associate with Atg5-Atg12. High-throughput quantitative mass spectrometry and endogenous protein-protein interaction revealed an NLRX1-interacting partner, mitochondrial Tu translation elongation factor (TUFM). TUFM interacted with Atg5-Atg12 and Atg16L1 and has similar functions as NLRX1 by inhibiting RLR-induced IFN-I but promoting autophagy. In the absence of NLRX1, increased IFN-I and decreased autophagy provide an advantage for host defense against vesicular stomatitis virus. This study establishes a link between an NLR protein and the viral-induced autophagic machinery via an intermediary partner, TUFM. © 2012 Elsevier Inc. Source

Haddad E.K.,VGTI Florida | Pantaleo G.,University of Lausanne
Current Opinion in HIV and AIDS | Year: 2012

Purpose of review: In the present review, we will provide the scientific rationale for applying systems biology to the development of vaccines and particularly HIV vaccines, the predictive power of systems biology on the vaccine immunological profile, the correlation between systems biology and the immunological functional profiles of different candidate vaccines, and the value of systems biology in the selection process of identifying the best-in-class candidate vaccines and in the decision process to move into in-vivo evaluation in clinical trials. Recent findings: Systems biology has been recently applied to the characterization of the protective yellow fever vaccine YF 17D and of seasonal flu vaccines. This has been instrumental in the identification of the components of the immune response that need to be stimulated by the vaccine in order to generate protective immunity. It is worth noting that a systems biology approach is currently being performed to identify correlates of immune protection of the RV144 Thai vaccine, the only known vaccine that showed modest protection against HIV reacquisition. Summary: Systems biology represents a novel and powerful approach to predict the vaccine immunological profile, to identify the protective components of the immune response, and to help in the selection process of the bestin-class vaccines to move into clinical development. © 2011 Wolters Kluwer Health. Source

Peretz Y.,Immune Carta Services | Cameron C.,VGTI Florida | Sekaly R.-P.,Immune Carta Services | Sekaly R.-P.,VGTI Florida
Current Opinion in HIV and AIDS | Year: 2012

Purpose of review: Several unique HIV-infected or HIV-resistant cohorts have been studied over the years to try and delineate the correlates of protection. Although several mechanisms have been put forward, studies aiming to integrate the different mechanisms into a comprehensive model are still lacking. Current systems biology approaches emphasize the importance of unifying independent datasets, provide tools that facilitate hypothesis formulation and testing, and direct us toward uncovering novel therapeutic targets by defining molecular networks perturbed during disease. This review will focus on the current findings that utilized systems biology techniques in order to identify correlates of protection from HIV disease progression and resistance to infection in unique cohorts of individuals as well as in nonhuman primate models of SIV infection. Recent findings: Using systems biology technologies and data analysis tools, the studies described herein have found that pathways implicated in survival, cell cycling, inflammation, and oxidative stress work in unison to limit pathology caused by chronic immune activation. This situation favors the survival of effector lymphocytes and limits the dissemination of viral particles in HIV elite controllers, exposed-uninfected individuals, and natural hosts of SIV infection. Summary: Systems and computational biology tools have clearly expanded our understanding of HIV pathogenesis by unifying independent observations and by giving us novel molecular targets to pursue. These molecular signatures have the potential to uncover correlates of protection in HIV disease and, in the era of personalized medicine, to determine predictive signatures of treatment efficacy and/or failure. © 2011 Wolters Kluwer Health. Source

Lewis M.G.,BIOQUAL Inc. | Dafonseca S.,VGTI Florida | Chomont N.,VGTI Florida | Palamara A.T.,University of Rome La Sapienza | And 10 more authors.
AIDS | Year: 2011

Objectives: A small pool of long-lived memory CD4 T cells harboring the retroviral genome is one main obstacle to HIV eradication. We tested the impact of the gold compound, auranofin, on phenotype and viability of CD4 + T cells in vitro, and on persistence of lentiviral reservoir cells in vivo. Design: In-vitro and in-vivo study. The pro-differentiating effect of auranofin was investigated in human primary CD4 + T cells, and its capacity to deplete the viral DNA (vDNA) reservoir was tested in a pilot study involving six SIVmac251-infected macaques with viral loads stably suppressed by antiretroviral therapy (ART) (tenofovir/emtricitabine/raltegravir). The study was then amplified by intensifying ART using darunavir/r and including controls under intensified ART alone. All therapies were eventually suspended and viro-immunological parameters were monitored over time. METHODS:: Cell subpopulations were quantitated by flow cytometry following proper hematological analyses. Viral load and cell-associated vDNA were quantitated by Taqman real-time PCR. Results: In naïve, central memory and transitional memory CD4 + T cells, auranofin induced both phenotype changes and cell death which were more pronounced in the memory compartment. In the pilot study in vivo, auranofin transiently decreased the cell-associated vDNA reservoir in peripheral blood. When ART was intensified, a sustained decrease in vDNA was observed only in auranofin-treated monkeys but not in controls treated with intensified ART alone. After therapy suspension, only monkeys that had received auranofin showed a deferred and subsequently blunted viral load rebound. Conclusion: These findings represent a first step towards a remission of primate lentiviral infections. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

Routy J.-P.,McGill University | Tremblay C.L.,University of Montreal | Angel J.B.,University of Ottawa | Trottier B.,Clinique Medicale lActuel | And 9 more authors.
HIV Medicine | Year: 2012

Objectives: Conflicting results have been reported regarding the ability of valproic acid (VPA) to reduce the size of HIV reservoirs in patients receiving suppressive highly active antiretroviral therapy (HAART). In a randomized multicentre, cross-over study, we assessed whether adding VPA to stable HAART could potentially reduce the size of the latent viral reservoir in CD4 T cells of chronically infected patients. Methods: A total of 56 virologically suppressed patients were randomly assigned either to receive VPA plus HAART for 16 weeks followed by HAART alone for 32 weeks (arm 1; n=27) or to receive HAART alone for 16 weeks and then VPA plus HAART for 32 weeks (arm 2; n=29). VPA was administered at a dose of 500mg twice a day (bid) and was adjusted to the therapeutic range. A quantitative culture assay was used to assess HIV reservoirs in CD4 T cells at baseline and at weeks 16 and 48. Results: No significant reductions in the frequency of CD4 T cells harbouring replication-competent HIV after 16 and 32 weeks of VPA therapy were observed. In arm 1, median (range) values of IU per log 10 billion (IUPB) cells were 2.55 (range 1.20-4.20), 1.80 (range 1.0-4.70) and 2.70 (range 1.0-3.90; P=0.87) for baseline, week 16 and week 48, respectively. In arm 2, median values of IUPB were 2.55 (range 1.20-4.65), 1.64 (range 1.0-3.94) and 2.51 (range 1.0-4.48; P=0.50) for baseline, week 16 and week 48, respectively. Conclusions: Our study demonstrates that adding VPA to stable HAART does not reduce the latent HIV reservoir in virally suppressed patients. © 2012 British HIV Association. Source

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