Schmidt B, Ashlock BM, Foster H et al.HIV-infected cells are major inducers of plasmacytoid dendritic cell interferon production, maturation, and migration. Virology 343:256-266

Department of Medicine, University of California, San Francisco, San Francisco, California, United States
Virology (Impact Factor: 3.32). 01/2006; 343(2):256-66. DOI: 10.1016/j.virol.2005.09.059
Source: PubMed


Plasmacytoid dendritic cells (PDC), natural type-1 interferon (IFN) producing cells, could play a role in the innate anti-HIV immune response. Previous reports indicated that PDC IFN production is induced by HIV. Our results show a more robust IFN induction when purified PDC (>95%) were exposed to HIV-infected cells. This effect was not observed with non-viable cells, DNA, and RNA extracted from infected cells, and viral proteins. The response was blocked by anti-CD4 and neutralizing anti-gp120 antibodies as well as soluble CD4. IFN induction by HIV-infected cells was also prevented by low-dose chloroquine, which inhibits endosomal acidification. PDC IFN release resulted in reduced HIV production by infected CD4+ cells, supporting an anti-HIV activity of PDC. Stimulated CD4+ cells induced PDC activation and maturation; markers for PDC migration (CCR7) were enhanced by HIV-infected CD4+ cells only. This latter finding could explain the decline in circulating PDC in HIV-infected individuals.

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Available from: Barbara Schmidt
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    • "However, we observed an inhibition of IFN-α production by NAb b12 (and its mutant LALA), consistent with previous reports using the same NAb26. Indeed, it was suggested that the inhibition of IFN-α production was the consequence of interaction between viral gp120 and cellular CD4263637. Interestingly, in our study, NAb VRC01 that recognizes the CD4 binding site (CD4bs) of the gp12038 and polyclonal IgG (that probably contains a large number of anti-CD4bs Ab)39, had almost no effect on IFN-α production by primary pDC while they inhibited the productive infection of the cells. As these Ab interact with the CD4bs of gp120, we may hypothesize that interaction leading to IFN-α production is not hindered by NAb VRC01 on primary pDC. "
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    ABSTRACT: Plasmacytoid dendritic cells (pDC) expressing FcγRIIa are antigen-presenting cells able to link innate and adaptive immunity and producing various cytokines and chemokines. Although highly restricted, they are able to replicate HIV-1. We determined the activity of anti-HIV-1 neutralizing antibodies (NAb) and non-neutralizing inhibitory antibodies (NNIAb) on the infection of primary pDC by HIV-1 primary isolates and analyzed cytokines and chemokines production. Neutralization assay was performed with primary pDC in the presence of serial antibodies (Ab) concentrations. In parallel, we measured the release of cytokines and chemokines by ELISA and CBA Flex assay. We found that NAb, but not NNIAb, inhibit HIV-1 replication in pDC. This inhibitory activity was lower than that detected for myeloid dendritic cells (mDC) infection and independent of FcγRIIa expressed on pDC. Despite the complete protection, IFN-α production was detected in the supernatant of pDC treated with NAb VRC01, 4E10, PGT121, 10-1074, 10E8, or polyclonal IgG44 but not with NAb b12. Production of MIP-1α, MIP-1β, IL-6, and TNF-α by pDC was also maintained in the presence of 4E10, b12 and VRC01. These findings suggest that pDC can be protected from HIV-1 infection by both NAb and IFN-α release triggered by the innate immune response during infection.
    Full-text · Article · Aug 2014 · Scientific Reports
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    • "In pDCs incubated with HIV in the presence of an anti-CD4 antibody, IFN a is markedly inhibited. However, co-receptor usage does not seem necessary for pDC activation by HIV (Beignon et al. 2005 ; Herbeuval et al. 2005a ; Schmidt et al. 2005 ; Haupt et al. 2008 ) . Further support of the necessity of CD4-gp120 binding to pDC to induce IFN a production has been supported by the fi nding that the degree of IFN a induction is correlated with the af fi nity of the virus to CD4 (Haupt et al. 2008 ) . "
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    ABSTRACT: Plasmacytoid dendritic cells (pDCs) are innate immune cells that are specialized to produce interferon-alpha (IFNα) and participate in activating adaptive immune responses. Although IFNα inhibits HIV-1 (HIV) replication in vitro, pDCs may act as inflammatory and immunosuppressive dendritic cells (DCs) rather than classical antigen-presenting cells during chronic HIV infection in vivo, contributing more to HIV pathogenesis than to protection. Improved understanding of HIV-pDC interactions may yield potential new avenues of discovery to prevent HIV transmission, to blunt chronic immune activation and exhaustion, and to enhance beneficial adaptive immune responses. In this chapter we discuss pDC biology, including pDC development from progenitors, trafficking and localization of pDCs in the body, and signaling pathways involved in pDC activation. We focus on the role of pDCs in HIV transmission, chronic disease progression and immune activation, and immunosuppression through regulatory T cell development. Lastly, we discuss potential future directions for the field which are needed to strengthen our current understanding of the role of pDCs in HIV transmission and pathogenesis.
    Full-text · Article · Jan 2013 · Advances in Experimental Medicine and Biology
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    • "The innate immune system is our first line of defense against invading microorganisms while the adaptive immune system acts as a second line of defense and also affords protection against reexposure to the same pathogen. One of the hallmarks of the innate immune response is the production of the antiviral cytokine type I IFN (IFN-α and β): these factors inhibit viral replication and spreading [1]. Plasmacytoid dendritic cells (pDC) are the most potent IFNα-producing cells [2] [3] and serve as an essential link between innate and adaptive immunity [4]. "
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    ABSTRACT: Despite variability, the majority of HIV-1-infected individuals progress to AIDS characterized by high viral load and massive CD4+ T-cell depletion. However, there is a subset of HIV-1-positive individuals that does not progress and spontaneously maintains an undetectable viral load. This infrequent patient population is defined as HIV-1 controllers (HIV controllers), and represents less than 1% of HIV-1-infected patients. HIV-1-specific CD4+ T cells and the pool of central memory CD4+ T cells are also preserved despite immune activation due to HIV-1 infection. The majority of HIV controllers are also defined by the absence of massive CD4+ T-cell depletion, even after 10 years of infection. However, the mechanisms involved in protection against HIV-1 disease progression have not been elucidated yet. Controllers represent a heterogeneous population; we describe in this paper some common characteristics concerning innate immune response and CD4+ T cells of HIV controllers.
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