Herpes Simplex Virus Type 2 Enhances HIV-1 Susceptibility by Affecting Langerhans Cell Function

Jong, Marein A. W. P. de; Witte, Lot de; Taylor, Maureen E.; Geijtenbeek, Teunis B. H.

doi:10.4049/jimmunol.0904137

Cited by 67 publications

(80 citation statements)

References 45 publications

(89 reference statements)

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“…This is not specific to MV, because antibodies targeted to Langerin are also presented to CD4 1 T cells. Since Langerin is also an attachment receptor for HIV-1 [10], Herpes Simplex Virus-2 [33] and fungi [34], our data support a role for Langerin as a pathogen receptor. The MV envelope glycoproteins F and H contain high mannose structures [35] that are likely recognized by Langerin, similarly as shown for C-type lectin DC-SIGN [24].…”

Section: Discussionsupporting

confidence: 65%

Human Langerhans cells capture measles virus through Langerin and present viral antigens to CD4⁺ T cells but are incapable of cross‐presentation

et al. 2011

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Langerhans cells (LCs) are a subset of DCs that reside in the upper respiratory tract and are ideally suited to sense respiratory virus infections. Measles virus (MV) is a highly infectious lymphotropic and myelotropic virus that enters the host via the respiratory tract. Here, we show that human primary LCs are capable of capturing MV through the C-type lectin Langerin. Both immature and mature LCs presented MV-derived antigens in the context of HLA class II to MV-specific CD4 1 T cells. Immature LCs were not susceptible to productive infection by MV and did not present endogenous viral antigens in the context of HLA class I. In contrast, mature LCs could be infected by MV and presented de novo synthesized viral antigens to MV-specific CD8 1 T cells. Notably, neither immature nor mature LCs were able to cross-present exogenous UV-inactivated MV or MV-infected apoptotic cells. The lack of direct infection of immature LCs, and the inability of both immature and mature LCs to crosspresent MV antigens, suggest that human LCs may not be directly involved in priming MV-specific CD8 1 T cells. Immune activation of LCs seems a prerequisite for MV infection of LCs and subsequent CD8 1 T-cell priming via the endogenous antigen presentation pathway. Eur. J. Immunol. 2011. 41: 2619-2631 DOI 10.1002 Immunity to infection 2619 molecules, a process referred to as cross-presentation which is thought to be important in both viral and tumor immunity [2,3]. It is becoming evident that different DC subsets have specialized functions in anti-viral immunity, e.g. by inducing preferentially CD4 1 or CD8 1 T-cell responses or by inducing innate immunity against pathogens [4,5]. Langerhans cells (LCs) are a subset of DCs that are, in humans, characterized by expression of CD1a, the C-type lectin Langerin and the presence of Birbeck granules [6]. LCs reside in the epidermis and stratified epithelial tissues [7][8][9]. Recently, we have shown that LCs form a barrier against HIV-1; LCs capture HIV-1 through Langerin, resulting in internalization of HIV-1 into Birbeck granules and preventing subsequent HIV-1 transmission [10]. However, little is known about the role of human LCs and Langerin in antigen presentation.Capture of exogenous antigens by LCs leads to induction of CD4 1 T-cell responses [11][12][13]. However, the ability of LCs to cross-present exogenous antigens to CD8 1 T cells has been debated [14][15][16][17]. Klechevsky et al. [13] have shown that in vitrogenerated human LCs from either CD34 1 cells or monocytes are capable of cross-presenting influenza-virus proteins to CD8 1 T cells. However, these in vitro-generated LCs might be different from primary immature LCs.Here, we have investigated the antigen capture and presentation capacity of human primary LCs during measles virus (MV) infection. MV is the causative agent of measles, which remains an important cause of morbidity and mortality in developing countries. MV is a lymphotropic and myelotropic virus and DCs have been implicated in its transmission [18,19]. MV is on...

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Section: Discussionsupporting

confidence: 65%

Human Langerhans cells capture measles virus through Langerin and present viral antigens to CD4⁺ T cells but are incapable of cross‐presentation

et al. 2011

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“…However, TNF-a has different effects on DCs infected de novo, for example, it induces maturation in MDDCs, which eventually reduces their susceptibility to productive HIV-1 infection (26,48). The balance between inhibition of HIV-1 production by IFN-b and stimulation by TNF-a after live and UV inactivated HSV-2 stimulation also explains apparent differences from two previous reports (26,46). One of these reports (46) discounted any effect of TNF-a in enhancing HIV-1 production by LCs, but this is explained by the other, which showed that MDDCs exposed to UV HSV-2 produced greater levels of IFN-b but lower levels of TNF-a than those exposed to infectious HSV-2 (26).…”

Section: Discussioncontrasting

confidence: 54%

“…The balance between inhibition of HIV-1 production by IFN-b and stimulation by TNF-a after live and UV inactivated HSV-2 stimulation also explains apparent differences from two previous reports (26,46). One of these reports (46) discounted any effect of TNF-a in enhancing HIV-1 production by LCs, but this is explained by the other, which showed that MDDCs exposed to UV HSV-2 produced greater levels of IFN-b but lower levels of TNF-a than those exposed to infectious HSV-2 (26). We found similar effects on TNF-a and IFN-b in LCs and, importantly, no effect of UV-HSV-2 on HIV-1 coinfection; infectious HSV-2 was required.…”

Section: Discussioncontrasting

confidence: 47%

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Herpes Simplex Virus Type 2–Infected Dendritic Cells Produce TNF-α, Which Enhances CCR5 Expression and Stimulates HIV Production from Adjacent Infected Cells

Marsden

Donaghy

Bertram

et al. 2015

The Journal of Immunology

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Prior HSV-2 infection enhances the acquisition of HIV-1 >3-fold. In genital herpes lesions, the superficial layers of stratified squamous epithelium are disrupted, allowing easier access of HIV-1 to Langerhans cells (LC) in the epidermis and perhaps even dendritic cells (DCs) in the outer dermis, as well as to lesion infiltrating activated T lymphocytes and macrophages. Therefore, we examined the effects of coinfection with HIV-1 and HSV-2 on monocyte-derived DCs (MDDC). With simultaneous coinfection, HSV-2 significantly stimulated HIV-1 DNA production 5-fold compared with HIV-1 infection alone. Because <1% of cells were dually infected, this was a field effect. Virus-stripped supernatants from HSV-2–infected MDDCs were shown to enhance HIV-1 infection, as measured by HIV-1–DNA and p24 Ag in MDDCs. Furthermore these supernatants markedly stimulated CCR5 expression on both MDDCs and LCs. TNF-α was by far the most prominent cytokine in the supernatant and also within HSV-2–infected MDDCs. HSV-2 infection of isolated immature epidermal LCs, but not keratinocytes, also produced TNF-α (and low levels of IFN-β). Neutralizing Ab to TNF-α and its receptor, TNF-R1, on MDDCs markedly inhibited the CCR5-stimulating effect of the supernatant. Therefore, these results suggest that HSV-2 infection of DCs in the skin during primary or recurrent genital herpes may enhance HIV-1 infection of adjacent DCs, thus contributing to acquisition of HIV-1 through herpetic lesions.

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“…Several mechanisms for this increased susceptibility have been proposed. For instance, the formation of pustules and ulcers by genital herpes may facilitate HIV-1 entry into mucosal tissues (10,11). Analyses of biopsies of HSV-2 lesions from patients revealed that HSV-2 reactivation resulted in an influx of activated CD4 + T cells, which may facilitate HIV-1 infection and subsequent dissemination (12,13).…”

mentioning

confidence: 99%

Herpes Simplex Virus Type 2 Infection of Human Epithelial Cells Induces CXCL9 Expression and CD4+ T Cell Migration via Activation of p38-CCAAT/Enhancer-Binding Protein-β Pathway

Huang

Luo

et al. 2012

The Journal of Immunology

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Recruitment of CD4+ T cells to infection areas after HSV-2 infection may be one of the mechanisms that account for increased HIV-1 sexual transmission. Lymphocytes recruited by chemokine CXCL9 are known to be important in control of HSV-2 infection in mice, although the underlying mechanism remains to be addressed. Based on our observation that CXCL9 expression is augmented in the cervical mucus of HSV-2–positive women, in this study we demonstrate that HSV-2 infection directly induces CXCL9 expression in primary cervical epithelial cells and cell lines, the principal targets of HSV-2, at both mRNA and protein levels. Further studies reveal that the induction of CXCL9 expression by HSV-2 is dependent upon a binding site for C/EBP-β within CXCL9 promoter sequence. Furthermore, CXCL9 expression is promoted at the transcriptional level through phosphorylating C/EBP-β via p38 MAPK pathway, leading to binding of C/EBP-β to the CXCL9 promoter. Chemotaxis assays indicate that upregulation of CXCL9 expression at the protein level by HSV-2 infection enhances the migration of PBLs and CD4+ T cells, whereas neutralization of CXCL9 or inhibition of p38-C/EBP-β pathway can significantly decrease the migration. Our data together demonstrate that HSV-2 induces CXCL9 expression in human cervical epithelial cells by activation of p38-C/EBP-β pathway through promoting the binding of C/EBP-β to CXCL9 promoter, which may recruit activated CD4+ T cells to mucosal HSV-2 infection sites and potentially increase the risk of HIV-1 sexual transmission.

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Herpes Simplex Virus Type 2 Enhances HIV-1 Susceptibility by Affecting Langerhans Cell Function

Cited by 67 publications

References 45 publications

Human Langerhans cells capture measles virus through Langerin and present viral antigens to CD4⁺ T cells but are incapable of cross‐presentation

Human Langerhans cells capture measles virus through Langerin and present viral antigens to CD4⁺ T cells but are incapable of cross‐presentation

Herpes Simplex Virus Type 2–Infected Dendritic Cells Produce TNF-α, Which Enhances CCR5 Expression and Stimulates HIV Production from Adjacent Infected Cells

Herpes Simplex Virus Type 2 Infection of Human Epithelial Cells Induces CXCL9 Expression and CD4+ T Cell Migration via Activation of p38-CCAAT/Enhancer-Binding Protein-β Pathway

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Herpes Simplex Virus Type 2 Enhances HIV-1 Susceptibility by Affecting Langerhans Cell Function

Cited by 67 publications

References 45 publications

Human Langerhans cells capture measles virus through Langerin and present viral antigens to CD4+ T cells but are incapable of cross‐presentation

Human Langerhans cells capture measles virus through Langerin and present viral antigens to CD4+ T cells but are incapable of cross‐presentation

Herpes Simplex Virus Type 2–Infected Dendritic Cells Produce TNF-α, Which Enhances CCR5 Expression and Stimulates HIV Production from Adjacent Infected Cells

Herpes Simplex Virus Type 2 Infection of Human Epithelial Cells Induces CXCL9 Expression and CD4+ T Cell Migration via Activation of p38-CCAAT/Enhancer-Binding Protein-β Pathway

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Human Langerhans cells capture measles virus through Langerin and present viral antigens to CD4⁺ T cells but are incapable of cross‐presentation

Human Langerhans cells capture measles virus through Langerin and present viral antigens to CD4⁺ T cells but are incapable of cross‐presentation