Takamitsu Matsuzawa

Antimicrobial Peptide LL-37 Produced by HSV-2-Infected Keratinocytes Enhances HIV Infection of Langerhans Cells

Herpes simplex virus (HSV)-2 shedding is associated with increased risk for sexually acquiring HIV. Because Langerhans cells (LCs), the mucosal epithelium resident dendritic cells, are suspected to be one of the initial target cell types infected by HIV following sexual exposure, we examined whether and how HSV-2 affects HIV infection of LCs. Although relatively few HSV-2/HIV-coinfected LCs were detected, HSV-2 dramatically enhanced the HIV susceptibility of LCs within skin explants. HSV-2 stimulated epithelial cell production of antimicrobial peptides (AMPs), including human β defensins and LL-37. LL-37 strongly upregulated the expression of HIV receptors in monocyte-derived LCs (mLCs), thereby enhancing their HIV susceptibility. Culture supernatants of epithelial cells infected with HSV-2 enhanced HIV susceptibility in mLCs, and this effect was abrogated by blocking LL-37 production. These data suggest that HSV-2 enhances sexual transmission of HIV by increasing HIV susceptibility of LCs via epithelial cell production of LL-37.

Oral Administration of the CCR5 Inhibitor, Maraviroc, Blocks HIV Ex Vivo Infection of Langerhans Cells within the Epithelium

TO THE EDITOR Preexposure prophylaxis (PrEP) with oral administration of an antiretroviral is a potential method for preventing acquisition of HIV. A controlled trial in men who have sex with men (the iPrEx trial) showed that daily oral use of tenofovir disoproxil fumarateemtricitabine (TDF-FTC; Truvada) reduced transmission rates by 44% (Grant et al., 2010). In addition, the HIV Prevention Trial Network (HPTN) 052 trial recently confirmed that antiretroviral treatment leads to 96% reduction in transmission among HIV-negative heterosexual partners of HIV-positive individuals (Cohen et al., 2011). Similar trials, however, with TDF-FTC (the FEM-PrEP trial) or TDF alone (the VOICE trial) were stopped because of poor outcomes (van der Straten et al., 2012). Different results among various trials, which used identical antiretroviral regimens, could be explained by varying compliance with drug use and/or varying drug concentration and activity within the exposed tissue (Patterson et al., 2011). Langerhans cells (LCs) are CCR5þ dendritic cells located within genital skin and mucosal epithelium (Lederman et al., 2006). In female rhesus macaques exposed intravaginally to simian immunodeficiency virus, up to 90% of initially infected target cells were LCs (Hu et al., 2000). Ex vivo experiments with human foreskin explants show that epidermal LCs are target cells for HIV, providing a likely explanation for why circumcision greatly reduces the probability of acquiring HIV (Ganor et al., 2010). LCs also express CD4 and CCR5, but not CXCR4, within the tissue and demonstrate the distinctive characteristics of emigrating from tissue to draining lymph nodes in order to interact with T cells after contact with pathogens (Kawamura et al., 2000). Indeed, epidermal LCs are readily infected ex vivo with R5 HIV, but not with X4 HIV, and promote high levels of infection upon interaction with cocultured CD4þ T cells (Kawamura et al., 2000; Ogawa et al., 2013). Thus, LCs probably have an important role in disseminating HIV soon after exposure to virus. Epidemiologic observations have found that the majority of HIV strains isolated from patients soon after initial infection are R5 HIV strains (i.e., they utilize CCR5; Lederman et al., 2006). Not surprisingly, individuals with homozygous defects in CCR5 are largely protected from sexually acquiring HIV (Lederman et al., 2006). In addition, three different CCR5-binding topically applied compounds protected female macaques from sexually acquiring simian/human immunodeficiency virus: the N-terminally modified chemokine analog PSC-RANTES, the small-molecule inhibitor CMPD167, and maraviroc (MVC) (Lederman et al., 2006; Veazey et al., 2010). In addition to topical application to vaginal mucosa, oral delivery of CMPD167 protected macaques from vaginal simian/human immunodeficiency virus challenge (Veazey et al., 2005). Given these data, orally administered MVC may prove to be particularly important in PrEP regimens, although its ability to prevent HIV acquisition is unknown. In the current study, 20 healthy volunteers were randomly divided into four equal groups; they received 300 mg of MVC orally twice daily for 1, 2, 3, or 14 days. To obtain epidermal tissues, all subjects underwent suction blistering of the skin before and 2 hours after the last MVC dose. All subjects had plasma and semen collected 2 hours after their last dose. MVC concentrations in serum, semen, and epidermal tissues were determined by using the liquid chromatography– mass spectometry method, as described previously (Takahashi et al., 2010). Mean concentration±SD in the epidermis was 21.91±13.80, 23.36± 13.28, and 31.54±20.61 nM for individuals taking drug for 1, 2, or 3 days (n1⁄45 for each), respectively. MVC concentrations tended to be higher with a longer dosing period. Consistent with recent data showing high levels of MVC in genital tissue (Dumond et al., 2009), these results indicate that MVC rapidly distributes into the skin at high concentrations. In addition, MVC was detected in semen of all subjects (Supplementary Figure S1 online). To understand how HIV traverses skin and genital mucosa, an ex vivo model was developed whereby resident LCs within epithelial tissue explants are exposed to HIV and then allowed to emigrate from tissue, thus mimicking conditions that occur after mucosal exposure to HIV (Kawamura et al., 2000; Ogawa et al., 2013). In this model, although relatively few productively infected LCs are identified, these cells induce high levels of HIV infection when cocultured with resting autologous CD4þ T cells (Kawamura et al., 2000). In preliminary experiments, HIV infection of LCs, as well as subsequent virus transmission from emigrated LCs to cocultured CD4þ T cells, was decreased in a dose-dependent manner when skin explants were pretreated with various concentrations of MVC before See related commentary on pg 2662

Case of primary cutaneous peripheral T-cell lymphoma, not otherwise specified, with characteristics of follicular helper T cells

We report a case of an 88‐year‐old woman with a decalvant, erythematous, ulcerated tumor extending from the right temporal to occipital region. Histopathological analysis revealed a dense infiltration of medium‐to‐large‐sized atypical cells throughout the entire dermis. The result of immunohistochemical analysis showed that the infiltrating T cells expressed programmed death‐1 (PD‐1), Bcl‐6 and CXCL13. Flow cytometry analysis showed that CD4+ PD‐1hi T cells also expressed CD10, inducible T‐cell co‐stimulator and CXCR5. On the basis of the clinical appearance and the histopathological findings, we diagnosed the patient with primary cutaneous peripheral T‐cell lymphoma, not otherwise specified. Recently, the concept of primary cutaneous follicular helper T (TFH)‐cell lymphoma was proposed, and in this case, tumor cells clearly expressed TFH‐cell markers. Therefore, we considered this case to be a variant of the entity. Although this entity is still provisional, this case supports the new concept.

Recruitment of plasmacytoid dendritic cells to skin regulates treatment responsiveness of actinic keratosis to imiquimod

Fig. 1. pDCs are recruited to IMQ-treated AK lesion and the number of pDCs recruited to clinical course. Left panel shows the duration of healing by tIMQ in total AK patients an pictures of AK treated by tIMQ in groups without or with inflammation. Representative im microscopic field (c) in AK lesions before and after IMQ treatment. Results are shown as m (d) Correlation between duration of AK clearance and number of BDCA-2+ pDCs in AK les

Immunological function of Langerhans cells in HIV infection

BACKGROUND Langerhans cells (LCs) are one of the initial target cells for HIV following sexual exposure and they are productively infected by HIV. HIV-infected LCs migrate to the draining lymph nodes (dLNs) and transmit the virus to CD4+ T cells, leading to the dissemination of HIV. In contrast with the role of LCs in initial HIV acquisition, little is known about the modulation of immune responses by HIV-infected LCs. OBJECTIVE We aimed to elucidate the induction of HIV-specific CD8+ T cells and regulatory T cells (Tregs), both of which play important roles in regulating the progression of HIV infection. METHODS We examined the inducibility of HLA-A*0201 restricted HIV-specific CD8+ T cells and Tregs by HIV-primed LCs or HIV-primed dendritic cells (DCs) as a control. RESULTS The number of HIV-specific CD8+ T cells induced by HIV-primed monocyte-derived LCs (mLCs) was significantly higher than that by HIV-primed monocyte-derived DCs (mDCs). Additionally, HIV-specific CD8+ T cells induced by HIV-primed mLCs produced more IFN-γ than HIV-nonspecific CD8+ T cells. HIV-primed human epidermal LCs also induced IFN-γ-producing HIV-specific CD8+ T cells. As for the induction of Tregs, HIV-primed mLCs and human epidermal LCs significantly impaired the induction of FoxP3hiCD45RA- effector Tregs than HIV-unprimed mLCs and human epidermal LCs. CONCLUSIONS HIV-primed LCs trigger beneficial immune responses against HIV infection through the increased induction of HIV-specific CD8+ T cells and the decreased induction of effector Tregs in the initial phase of HIV infection, thereby contributing to the prolonged onset of AIDS.

Case of folliculotropic mycosis fungoides with prominent loss of T‐cell antigens CD7 and CD26 in blood T cells

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Case of metastatic uveal melanoma in which an antitumor effect appeared after ipilimumab discontinuation due to autoimmune hypophysitis

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