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Review
. 2013 Jul;254(1):170-89.
doi: 10.1111/imr.12082.

Dendritic cell dysregulation during HIV-1 infection (VSports)

Elizabeth Miller  1 , Nina Bhardwaj
Affiliations
Review

Dendritic cell dysregulation during HIV-1 infection

Elizabeth Miller (V体育平台登录) et al. Immunol Rev. 2013 Jul.

Abstract

Dendritic cells (DCs) are a diverse subset of innate immune cells that are key regulators of the host response to human immunodeficiency virus-1 (HIV-1) infection. HIV-1 directly and indirectly modulates DC function to hinder the formation of effective antiviral immunity and fuel immune activation. This review focuses upon the differential dysregulation of myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) at various stages of HIV-1 infection providing insights into pathogenesis. HIV-1 evades innate immune sensing by mDCs resulting in suboptimal maturation, lending to poor generation of antiviral adaptive responses and contributing to T-regulatory cell (Treg) development. Dependent upon the stage of HIV-1 infection, mDC function is altered in response to Toll-like receptor ligands, which further hinders adaptive immunity and limits feasibility of therapeutic vaccine strategies. pDC interactions with HIV-1 are pleotropic, modulating immune responses on an axis between immunostimulatory and immunosuppressive VSports手机版. pDCs promote immune activation through an altered phenotype of persistent type I interferon secretion and weak antigen presentation capacity. Conversely, HIV-1 stimulates secretion of indolemine 2,3 dioxygenase (IDO) by pDCs resulting in Treg induction. An improved understanding of the roles and underlying mechanisms of DC dysfunction will be valuable to the development of therapeutics to enhance HIV-specific adaptive responses and to dampen immune activation. .

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Figures

Fig. 1
Fig. 1. mDC function at various stages of HIV-1 infection
mDC function is suppressed during viral ramp-up (Fiebig stages I/II) and then transitions to hyperresponsiveness to Toll-like receptor (TLR) ligation in the later Fiebig stages of AHI. During chronic infection, mDC function is again suppressed upon TLR ligation, but this is partially mitigated by suppressive ART.
Fig. 2
Fig. 2. Strategies to overcome myeloid DC (mDC) dysfunction during HIV-1 infection
Augmentation of mDC function can be carried out ex vivo through activation and antigen loading, followed by reintroduction of these modified cells to the patient as a form of adoptive immunotherapy (left). Alternatively, mDC function can be rescued in situ by mDC-targeting formulations that are capable of combating the suppressive milieu present during HIV-1 infection (right). Strategies include targeting mDCs by coupling HIV-protein to monoclonal antibodies toward endocytic receptors on mDCs, utilization of recombinant vectors that naturally target mDCs, or HIV-1 antigens co-formulated with mDC-activating adjuvants.
Fig. 3
Fig. 3. The contrary roles of plasmacytoid DCs (pDCs) in HIV-1 infection
HIV-1 stimulates pDCs to produce interferonα, which has antiviral functions, but persistent secretion also contributes to immune activation. HIV-1 induces pDCs to secrete IDO, which directs the formation of Tregs. Tregs have a dual role in dampening both immune activation but also myeloid DC activation and HIV-specific effector T-cell responses.
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