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.
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.
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.
Kulpa D.A.,VGTI Florida |
Lawani M.,VGTI Florida |
Cooper A.,VGTI Florida |
Peretz Y.,Caprion ImmuneCarta Services |
And 2 more authors.
Seminars in Immunology | Year: 2013
In the majority of HIV-1 infected individuals, the adaptive immune response drives virus escape resulting in persistent viremia and a lack of immune-mediated control. The expression of negative regulatory molecules such as PD-1 during chronic HIV infection provides a useful marker to differentiate functional memory T cell subsets and the frequency of T cells with an exhausted phenotype. In addition, cell-based measurements of virus persistence equate with activation markers and the frequency of CD4 T cells expressing PD-1. High-level expression of PD-1 and its ligands PD-L1 and PD-L2 are found on hematopoietic and non-hematopoietic cells, and are upregulated by chronic antigen stimulation, Type 1 and Type II interferons (IFNs), and homeostatic cytokines. In HIV infected subjects, PD-1 levels on CD4 and CD8 T cells continue to remain high following combination anti-retroviral therapy (cART). System biology approaches have begun to elucidate signal transduction pathways regulated by PD-1 expression in CD4 and CD8 T cell subsets that become dysfunctional through chronic TCR activation and PD-1 signaling. In this review, we summarize our current understanding of transcriptional signatures and signal transduction pathways associated with immune exhaustion with a focus on recent work in our laboratory characterizing the role of PD-1 in T cell dysfunction and HIV pathogenesis. We also highlight the therapeutic potential of blocking PD-1-PD-L1 and other immune checkpoints for activating potent cellular immune responses against chronic viral infections and cancer. © 2013 Elsevier Ltd.
Perrin H.,VGTI Florida |
Canderan G.,VGTI Florida |
Sekaly R.-P.,VGTI Florida |
Sekaly R.-P.,University of Montréal |
Trautmann L.,VGTI Florida
Current Opinion in HIV and AIDS | Year: 2010
Purpose of review: Following the evidence that T-cell responses are crucial in the control of HIV-1 infection, vaccines targeting T-cell responses were tested in recent clinical trials. However, these vaccines showed a lack of efficacy. This review attempts to define the qualitative and quantitative features that are desirable for T-cell-induced responses by vaccines. We also describe strategies that could lead to achievement of this goal. Recent Findings: Using the yellow fever vaccine as a benchmark of an efficient vaccine, recent studies identified factors of immune protection and more importantly innate immune pathways needed for the establishment of long-term protective adaptive immunity. Summary: To prevent or control HIV-1 infection, a vaccine must induce efficient and persistent antigen-specific T cells endowed with mucosal homing capacity. Such cells should have the capability to counteract HIV-1 diversity and its rapid spread from the initial site of infection. To achieve this goal, the activation of a diversified innate immune response is critical. New systems biology approaches will provide more precise correlates of immune protection that will pave the way for new approaches in T-cell-based vaccines. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Vandergeeten C.,VGTI Florida |
Fromentin R.,VGTI Florida |
Chomont N.,VGTI Florida
Cytokine and Growth Factor Reviews | Year: 2012
HIV persists in cellular and anatomical reservoirs during Highly Active Antiretroviral Therapy (HAART). In vitro studies as well as in vivo observations have identified cytokines as important factors regulating the immunological and virological mechanisms involved in HIV persistence. Immunosuppressive cytokines might contribute to the establishment of viral latency by dampening T cell activation and HIV production, thereby creating the necessary immuno-virological condition for the establishment of a pool of latently infected cells. Other cytokines that are involved in the maintenance of memory CD4+ T cells promote the persistence of these cells during HAART. Conversely, proinflammatory cytokines may favor HIV persistence by exacerbating low levels of ongoing viral replication in lymphoid tissues even after prolonged therapy. The ability of several cytokines to interfere with the molecular mechanisms responsible for HIV latency makes them attractive candidates for therapeutic strategies aimed at reducing the pool of latently infected cells. In this article, we review the role of cytokines in HIV persistence during HAART and discuss their role as potential eradicating agents. © 2012 Elsevier Ltd.
Boulassel M.-R.,McGill University |
Chomont N.,VGTI Florida |
Pai N.P.,McGill University |
Gilmore N.,McGill University |
And 3 more authors.
Journal of Clinical Virology | Year: 2012
Background: The level of HIV-1 integrated DNA in CD4 T cells was reported to predict the evolution of untreated HIV-1 infection independently of CD4 cell counts or plasma HIV-1 RNA levels. However, the relevance of reservoir level while on efficient antiretroviral therapy (ART) is still unknown. Objectives: To evaluate factors that may contribute to the establishment and maintenance of HIV-1 reservoir size in ART-treated HIV-1-infected adults with complete suppression of viremia. Study design: 35 subjects receiving ART with plasma HIV-1 RNA below the limit of detection for an average duration of 3.2 years were studied. A highly sensitive PCR was used to assess HIV-1 integrated DNA levels in sorted CD4 T cells. Results: The mean HIV-1 integrated DNA was 300±7copies/10 6 CD4 cells (range 10-1408). In univariate analysis, the levels of HIV-1 proviral DNA appeared to be independent of duration of HIV-1-infection, duration on ART, time since HIV-1 viral load was undetectable, delay between HIV-1 infection and starting ART, or viral load before starting ART. Conversely, CD4 T cell nadir, CD4/CD8 ratio and, to lesser degree, CD4 T cell counts were inversely associated with HIV-1 proviral DNA levels. In multivariate analysis, only CD4 T cell nadir significantly predicted levels of HIV-1 proviral DNA (P=0.025). Conclusions: CD4 T cell nadir strongly predicted reservoir size independently of other factors in HIV-1-infected adults with complete suppression of viremia. Collectively, these results indicate that the extent of CD4 T cell depletion before ART drives the size of the viral reservoir after prolonged therapy. © 2011 Elsevier B.V.
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.
Kulpa D.A.,VGTI Florida |
Brehm J.H.,VGTI Florida |
Fromentin R.,VGTI Florida |
Cooper A.,VGTI Florida |
And 4 more authors.
Immunological Reviews | Year: 2013
A major challenge in the development of a cure for human immunodeficiency virus (HIV) has been the incomplete understanding of the basic mechanisms underlying HIV persistence during antiretroviral therapy. It is now realized that the establishment of a latently infected reservoir refractory to immune system recognition has thus far hindered eradication efforts. Recent investigation into the innate immune response has shed light on signaling pathways downstream of the immunological synapse critical for T-cell activation and establishment of T-cell memory. This has led to the understanding that the cell-to-cell contacts observed in an immunological synapse that involve the CD4+ T cell and antigen-presenting cell or T-cell-T-cell interactions enhance efficient viral spread and facilitate the induction and maintenance of latency in HIV-infected memory T cells. This review focuses on recent work characterizing the immunological synapse and the signaling pathways involved in T-cell activation and gene regulation in the context of HIV persistence. © 2013 The Authors. Immunological Reviews published by John Wiley & Sons Ltd.