A cryptic sensor for HIV-1 activates antiviral innate immunity in dendritic cells

Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.
Nature (Impact Factor: 42.35). 09/2010; 467(7312):214-7. DOI: 10.1038/nature09337
Source: PubMed

ABSTRACT Dendritic cells serve a key function in host defence, linking innate detection of microbes to activation of pathogen-specific adaptive immune responses. Whether there is cell-intrinsic recognition of human immunodeficiency virus (HIV) by host innate pattern-recognition receptors and subsequent coupling to antiviral T-cell responses is not yet known. Dendritic cells are largely resistant to infection with HIV-1, but facilitate infection of co-cultured T-helper cells through a process of trans-enhancement. Here we show that, when dendritic cell resistance to infection is circumvented, HIV-1 induces dendritic cell maturation, an antiviral type I interferon response and activation of T cells. This innate response is dependent on the interaction of newly synthesized HIV-1 capsid with cellular cyclophilin A (CYPA) and the subsequent activation of the transcription factor IRF3. Because the peptidylprolyl isomerase CYPA also interacts with HIV-1 capsid to promote infectivity, our results indicate that capsid conformation has evolved under opposing selective pressures for infectivity versus furtiveness. Thus, a cell-intrinsic sensor for HIV-1 exists in dendritic cells and mediates an antiviral immune response, but it is not typically engaged owing to the absence of dendritic cell infection. The virulence of HIV-1 may be related to evasion of this response, the manipulation of which may be necessary to generate an effective HIV-1 vaccine.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Myeloid dendritic cells (DCs) can capture HIV-1 via the receptor CD169/Siglec-1 that binds to the ganglioside, GM3, in the virus particle membrane. In turn, HIV-1 particles captured by CD169, an I-type lectin, whose expression on DCs is enhanced upon maturation with LPS, are protected from degradation in CD169+ virus-containing compartments (VCCs) and disseminated to CD4+ T cells, a mechanism of DC-mediated HIV-1 trans-infection. In this study, we describe the mechanism of VCC formation and its role in immune evasion mechanisms of HIV-1. We find HIV-1-induced formation of VCCs is restricted to myeloid cells, and that the cytoplasmic tail of CD169 is dispensable for HIV-1 trafficking and retention within VCCs and subsequent trans-infection to CD4+ T cells. Interestingly, introduction of a di-aromatic endocytic motif in the cytoplasmic tail of CD169 that results in endocytosis of HIV-1 particles, suppressed CD169-mediated HIV-1 trans-infection. Furthermore, super-resolution microscopy revealed close association of CD169 and HIV-1 particles in surface-accessible but deep plasma membrane invaginations. Intriguingly, HIV-1 particles in deep VCCs were inefficiently accessed by anti-gp120 broadly neutralizing antibodies, VRC01 and NIH45-46 G54W, and thus were less susceptible to neutralization. Our study suggests that HIV-1 capture by CD169 can provide virus evasion from both innate (phagocytosis) and adaptive immune responses.
    PLoS Pathogens 03/2015; 11(3):e1004751. DOI:10.1371/journal.ppat.1004751 · 8.06 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hematopoietic gene therapy has tremendous potential to treat human disease. Nevertheless, for gene therapy to be efficacious, effective gene transfer into target cells must be reached without inducing detrimental effects on their biological properties. This remains a great challenge for the field as high vector doses and prolonged ex-vivo culture conditions are still required to reach significant transduction levels of clinically relevant human hematopoietic stem and progenitor cells (HSPC) while other potential target cells such as primary macrophages can hardly be transduced. The reasons behind poor permissiveness of primary human hematopoietic cells to gene transfer partly reside in the retroviral origin of lentiviral vectors (LVs). In particular, host antiviral factors referred to as restriction factors (RFs) targeting the retroviral life cycle can hamper LV transduction efficiency. Furthermore, LV may activate innate immune sensors not only in differentiated hematopoietic cells but also in HSPCs, with potential consequences on transduction efficiency as well as their biological properties. Therefore, better understanding of the vector-host interactions in the context of hematopoietic gene transfer is important for the development of safer and more efficient gene therapy strategies. In this review, we briefly summarize the current knowledge regarding innate immune recognition of lentiviruses in primary human hematopoietic cells as well as discuss its relevance for LV-based ex-vivo gene therapy approaches.
    Human gene therapy 03/2015; DOI:10.1089/hum.2015.036 · 3.62 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: HIV-1 replicates in immune cells that normally respond to incoming viruses and induce antiviral immune responses. Under this constant surveillance, how HIV-1 interacts with the host to escape immune control and causes immunopathology is still being untangled. Recently, a series of HIV-1 interactions with innate sensors of viruses expressed by immune target cells have been identified. Here, we review the HIV-1 factors that escape, engage and regulate these innate immune sensors. We discuss the general principles of these interactions as well as the remarkable cell-type specificity of the regulatory mechanisms and their resulting immune responses. Innate sensors directly intersect viral replication with immunity, and understanding their triggering, or lack thereof, improves our ability to design immune interventions. Copyright © 2015 Elsevier B.V. All rights reserved.
    Current Opinion in Virology 02/2015; 11C:55-62. DOI:10.1016/j.coviro.2015.01.013 · 6.30 Impact Factor

Full-text (2 Sources)

Available from
May 29, 2014