Differential Susceptibility to Human Immunodeficiency Virus Type 1 Infection of Myeloid and Plasmacytoid Dendritic Cells

Smed‐Sörensen, Anna; Loré, Karin; Vasudevan, Jayanand; Louder, Mark K.; Andersson, Jan; Mascola, John R.; Spetz, Anna-Lena; Koup, Richard A.

doi:10.1128/jvi.79.14.8861-8869.2005

Cited by 191 publications

(216 citation statements)

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“…This study was approved by the ethical committee at the Karolinska Institutet, Stockholm, Sweden, and the NIH, Bethesda, MD, USA. Our sorting procedures for direct isolation of DCs from blood have been described previously (Lore et al, 2003(Lore et al, , 2007Smed-Sorensen et al, 2005). DCs were cultured in complete medium composed of RPMI 1640 and 10 % fetal calf serum (FCS; Sigma-Aldrich).…”

Section: Methodsmentioning

confidence: 99%

Adenovirus serotype 5 infects human dendritic cells via a coxsackievirus–adenovirus receptor-independent receptor pathway mediated by lactoferrin and DC-SIGN

Adams

Bond

Havenga

et al. 2009

Journal of General Virology

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The coxsackievirus-adenovirus receptor (CAR) is the described primary receptor for adenovirus serotype 5 (Ad5), a common human pathogen that has been exploited as a viral vector for gene therapy and vaccination. This study showed that monocytes and dendritic cells (DCs), such as freshly isolated human blood myeloid DCs, plasmacytoid DCs and monocyte-derived DCs, are susceptible to recombinant Ad5 (rAd5) infection despite their lack of CAR expression. Langerhans cells and dermal DCs from skin expressed CAR, but blocking CAR only partly decreased rAd5 infection, together suggesting that other receptor pathways mediate viral entry of these cells. Lactoferrin (Lf), an abundant protein in many bodily fluids known for its antiviral and antibacterial properties, promoted rAd5 infection in all cell populations except plasmacytoid DCs using a CAR-independent process. Lf caused phenotypic differentiation of the DCs, but cell activation played only a minor role in the increase in infection frequencies. The C-type lectin receptor DC-SIGN facilitated viral entry of rAd5-Lf complexes and this was dependent on highmannose-type N-linked glycans on Lf. These results suggest that Lf present at high levels at mucosal sites can facilitate rAd5 attachment and enhance infection of DCs. A better understanding of the tropism and receptor mechanisms of Ad5 may help explain Ad5 pathogenesis and guide the engineering of improved rAd vectors. INTRODUCTIONAdenoviruses are frequent causes of acute upper respiratory tract infections and can be responsible for ocular and gastrointestinal illnesses in humans. They have also been exploited for the development of replication-incompetent viral vectors because their genomes allow large inserts of expression cassettes, thereby offering efficient gene delivery. Recombinant adenoviruses (rAds), serotype 5 (rAd5) in particular, are commonly used vectors for gene therapy and vaccination trials (Barouch & Nabel, 2005;McConnell & Imperiale, 2004;Tatsis & Ertl, 2004). The primary receptor described for infection of most Ad species (A, C, D, E and F) is the coxsackievirus and adenovirus receptor (CAR) (Bergelson et al., 1997;Roelvink et al., 1998;Tomko et al., 1997). As currently understood, infection of Ad5 (species C) involves binding of the viral fiber knob to CAR on the target cells (Roelvink et al., 1996), followed by an interaction between the viral penton base with a v integrins on the cell surface (Wickham et al., 1993). This allows virus-receptor complexes to enter clathrin-coated pits via endocytosis Wang et al., 1998;Wickham et al., 1993). Efficient infection of Ad5 via CAR has mainly been demonstrated in vitro using immortalized cell lines with well-exposed CAR. However, CAR is naturally expressed in tight junctions between cells and therefore et al., 2007). In this study, we investigated the involvement of CAR and the influence of Lf in rAd5 infection in relevant primary human APC populations from both blood and skin. METHODSIsolation of blood DCs. This study was approved by the ethical commi...

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Section: Methodsmentioning

confidence: 99%

Adenovirus serotype 5 infects human dendritic cells via a coxsackievirus–adenovirus receptor-independent receptor pathway mediated by lactoferrin and DC-SIGN

Adams

Bond

Havenga

et al. 2009

Journal of General Virology

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“…Differential restoration of mDCs and pDCs after HAART treatment is therefore not only observed in terms of the quantities present in the peripheral blood, but also in their cytokine release capabilities. Such a dichotomy in the response to HAART treatment between DC subsets is not yet understood; however, it may be associated with differing susceptibility of these two subsets to infection by R5 viruses (18,19).…”

Section: Restoration Of Circulating Impaired Mdcs and Pdcs Correlatedmentioning

confidence: 99%

“…Based on phenotypic and functional characterizations, two distinct circulating DC subsets have been identified in humans, myeloid (mDCs) and plasmacytoid DCs (pDCs). Both populations were found to be impaired in HIV-1-infected patients (12)(13)(14)(15)(16)(17) and are susceptible to infection by both R5 and X4 HIV-1 isolates, although mDCs are more efficiently infected by R5 isolates (18,19). Along with CD4 T cell counts and decreased IFN-␣ production, pDC counts are considered to be independent predictors of clinical disease progression and the onset of opportunistic infections (12,13,16,17).…”

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confidence: 99%

Differential Restoration of Myeloid and Plasmacytoid Dendritic Cells in HIV-1-Infected Children after Treatment with Highly Active Antiretroviral Therapy

Zhang

Zhao

et al. 2006

The Journal of Immunology

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Numerical and functional deficits in myeloid (mDC) and plasmacytoid dendritic cell (pDC) subsets have been found in both adult and pediatric HIV-1 carriers. Whether these impaired DC subsets can be restored after treatment with highly active antiretroviral therapy (HAART) is currently unknown, especially in HIV-1-infected children. In this report, we characterized mDC and pDC subsets in 18 HIV-1-infected children who received HAART treatment and compared them with those in 6 untreated HIV-1-infected children and 27 HIV-1-uninfected healthy children. Among children treated with HAART, 11 were found to suppress HIV-1 replication successfully below the detection limit (HAART-suppressed group) while the remaining 7 failed (HAART-failure group). In HAART-suppressed children, a gradual and complete restoration of the frequency and function of mDCs was observed while the recovery of pDCs was only partial. However, mDC and pDC subsets in HARRT failure children were indistinguishable from the HAART-naive infected children. We also found that mDC frequency and IFN-α-releasing capacity of pDC positively correlated with CD4 T cell percentages in all HIV-1-infected children. In HAART-naive children, the mDC frequency correlated the HIV-1-specific CTL frequency. Our findings suggest that HAART has a differential impact on the restoration of mDC and pDC subsets. These findings may help guide the development of HIV-1-specific immune therapy aimed at fully restoring host immune function in chronically HIV-1-infected children.

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“…HIV infection of DC also affects their function in more subtle ways. Recent studies show that when a substantial proportion of DC or LC are infected they undergo partial maturation and enhanced migration [35,41,42]. The partial maturation is sufficient to enhance T-cell stimulation and might also enhance viral transfer, thus affecting both viral production and anti-viral immunity.…”

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confidence: 99%

Langerhans cells and viral immunity

2008

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Langerhans cells (LC) are a unique dendritic cell subset that are located in mucosal stratified squamous epithelium and skin epidermis. Their location is ideally suited for their function as antigen presenting cells that capture invading viruses and induce anti-viral immunity. However, it is becoming evident that the interaction between LC and viruses can result in different responses, depending on the virus and the receptors involved. Here we will discuss the recent data on the similarities and differences in roles of LC in viral immunity to and infection with HIV, herpes simplex and varicella-zoster virus. Although all three viruses interact with LC during initial infection, the effects can be quite different, reflecting differences in biology and pathogenesis. Key words: Dendritic cells Á Langerhans cells Á Infectious diseases Á HIV Á HerpesvirusesSee accompanying mini-review by Kaplan et al. Biology of LC and interactions with virusesThe resident epidermal dendritic cells (DC), Langerhans cells (LC), form a tight network with each other and with the surrounding keratinocytes via E-cadherin in the skin or mucosal stratified squamous epithelium. In the anogenital region they are distributed throughout the anogenital skin and mucosa including vagina, ectocervix as well as male foreskin. In stratified squamous epithelium, LC overlie interstitial or dermal DC [1]. LC can repopulate from local and blood-borne precursors (reviewed by Kaplan et al. in this issue [2]). Similar to other myeloid DC, LC are able to bridge innate and adaptive immunity. They are able to interact directly with microorganisms at the periphery to produce effector cytokines and initiate or restimulate activation of T and B lymphocytes through antigen presentation. LC express different pattern recognition receptors such as C-type lectin receptors (CLR) and Toll-like receptors (TLR), to bind and capture pathogens. These interactions result in activation of intracellular signalling pathways leading to LC activation and cytokine induction. The CLR expressed by skin DC differ by site: Langerin by epidermal LC and DC-SIGN and mannose receptor by dermal DC. LC like other migratory DC are in an immature, highly endocytic state while sessile in the skin/mucosa. However after pathogen binding to TLR and uptake, LC become mature and migratory, downregulating their endocytic and antigen processing capacity. Mature LC migrate to the lymph nodes where they are directly or indirectly involved in presentation of pathogenderived antigens on MHC Class I and II to T cells, resulting in activation of antigen-specific T cells [2][3][4]. Recent studies have raised the possibility that LC may have an immunosuppressive role [5][6][7]. Kaplan et al. [2] showed that contact hypersensitivity was amplified on LC ablation, while Cumberbatch et al.[5] found defective LC mobilisation in patients with psoriasis. Immunosuppression rather than stimulation could be explained, in part, by the maturational process associated with LC migration during steady-state conditions. Jian...

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Differential Susceptibility to Human Immunodeficiency Virus Type 1 Infection of Myeloid and Plasmacytoid Dendritic Cells

Abstract: Human immunodeficiency virus type 1 (HIV-1) infection of dendritic cells (DCs

Cited by 191 publications

References 44 publications

Adenovirus serotype 5 infects human dendritic cells via a coxsackievirus–adenovirus receptor-independent receptor pathway mediated by lactoferrin and DC-SIGN

Adenovirus serotype 5 infects human dendritic cells via a coxsackievirus–adenovirus receptor-independent receptor pathway mediated by lactoferrin and DC-SIGN

Differential Restoration of Myeloid and Plasmacytoid Dendritic Cells in HIV-1-Infected Children after Treatment with Highly Active Antiretroviral Therapy

Langerhans cells and viral immunity

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