VIN may be human papillomavirus (HPV)-related classic VIN or -unrelated VIN. The former is by far the most frequent vulvar cancer precursor. It occurs in adult women and tends to be multi-focal. It is caused by high-risk HPV (HR-HPV) types, essentially type 16, and histologically is made of poorly selleck kinase inhibitor to undifferentiated basal cells and/or highly atypical squamous epithelial cells [1]. The involvement

of the entire thickness of the epithelium defines grade 3 of the disease. The disease progresses towards invasion in about 3% of treated patients and 9% of untreated patients, according to a review of more than 3000 cases [2]. Classic VIN can also regress spontaneously [3] in young women presenting with multi-focal pigmented papular lesions. Previously, we studied a patient who presented with multi-focal classic VIN and showed complete clearance of viral lesions 8 months after disease onset and 2 months after electrocoagulation of less than 50% of the classic VIN lesions [4]. Immunohistochemical

study of her initial vulvar biopsy revealed a marked dermal infiltrate containing a majority of CD4+ T lymphocytes and an epidermal infiltrate made up of both CD4+ and CD8+ T cells. She also showed a proliferating response against one peptide from E6 protein and a high-frequency anti-E6 and anti-E7 effector blood T cells by ex vivo enzyme-linked immunospot–interferon-γ (ELISPOT–IFN-γ) assay Epigenetics activator just before clinical regression. Such a study of blood cellular immune responses, together with the analysis of vulvar biopsies obtained simultaneously

and correlated with clinical outcome, has not been reported previously. In an anti-HPV vaccine trial conducted by Davidson et al.[5], classic VIN lesions regressed completely in a patient following vaccination. Interestingly, immunostaining of vulvar biopsy prior to the vaccine showed a marked CD4+ and CD8+ T lymphocyte infiltrate of both epithelial and subepithelial sheets. It may be speculated whether the regression of these patient lesions could be related to a spontaneous regression. Therefore, the observation of a CD4+ and CD8+ infiltrate within subepithelial and epithelial sheets in the biopsy and the visualization of very strong blood anti-HPV T cell responses in patients with classic VIN could be predictive of spontaneous clinical outcome. medroxyprogesterone It may also be thought that high numbers of blood CD4+ and CD8+ lymphocytes after therapeutic vaccination could allow clearance of HPV-16 lesions in classic VIN, assuming that anti-HPV vaccine-induced T effector cells could home into the HPV cutaneous and mucosal lesions. In the present study, we assessed cellular responses against HPV-16 E6 and E7 peptides in 16 patients presenting with classic VIN with the aim of mapping and characterizing the highest immunogenic regions from these proteins as potential candidates for a peptidic therapeutic vaccination.

Methods: Using Western analysis and immunohistochemistry

we evaluated post mortem frontal cerebral cortex from patients with severe AD (mean age 76 years, range 66–91, n = 11, all male), and from control cases without serious central nervous system illness (mean age 77 years, range 61–95, n = 12, all male). We also examined brains of Tg2576 transgenic mice (males, aged 16–21 months), a model for chronic amyloid-induced brain injury. Results: Immunohistochemical labelling showed DAPK1 expression in cortical neurones of human cortex and axonal tracts within subcortical white matter, both in AD and in control Deforolimus price brains. Western analysis confirmed DAPK1 expression in all samples, although expression was very low in some control cases. DAPK1 abundance in the AD group was not significantly different from that in controls (P = 0.07, Mann–Whitney test). In brains of Tg2576 mice DAPK1 abundance was very similar to that in wild-type littermates (P = 0.96, Mann–Whitney test). Conclusion: We found that DAPK1 was expressed in neurones of aged human frontal cortex,

both in AD and in control cases. “
“Recent evidence has placed Target Selective Inhibitor Library nmr the unfolded protein response (UPR) at the centre of pathological processes leading to neurodegenerative disease. The translational repression caused by UPR activation starves neurons of the essential proteins they need to function and survive. Restoration of protein synthesis, via genetic selleckchem or pharmacological means is neuroprotective in animal models, prolonging survival. This is of great interest due to the observation of UPR activation in the post-mortem brains of patients with Alzheimer’s, Parkinson’s, tauopathies and prion diseases. Protein synthesis is also an

essential step in the formation of new memories. Restoring translation in disease or increasing protein synthesis from basal levels has been shown to improve memory in numerous models. As neurodegenerative diseases often present with memory impairments, targeting the UPR to both provide neuroprotection and enhance memory provides an extremely exciting novel therapeutic target. “
“R. Paudel, J. Hardy, T. Revesz, J. L. Holton and H. Houlden (2012) Neuropathology and Applied Neurobiology38, 520–534 Genetics and neuropathology of primary pure dystonia Neuropathology has been the key to understanding the aetiology of many neurological disorders such as Alzheimer’s disease, Parkinson’s disease, frontotemporal degeneration and cerebellar ataxias.

When the animals were deeply anaesthetized blood was obtained by cardiac puncture of the right ventricle. Bronchoalveolar lavage (BAL) was performed by instilling 0·25 ml PBS through the tracheal cannula, followed by gentle aspiration and repeated with 0·2 ml PBS. Finally, one femur was cut at the epiphysis and the BM cells were flushed with 2 ml PBS. Bronchoalveolar lavage fluid and bone marrow.  Samples of BALF and BM were centrifuged at 300 g for 10 min at 4°. The BAL supernatant

was saved for eotaxin-2 measurement and stored at − 80° until analysis. The cells were resuspended with 0·03% BSA in PBS. The total cell numbers in BAL and BM were determined using standard haematological procedures. Cytospins selleck chemicals of BAL and BM were prepared and stained with May–Grünwald–Giemsa for differential cell counts by counting 300–500 cells using a light microscope (Zeiss Axioplan 2; Carl Zeiss, Jena, Germany). The cells were identified using standard morphological criteria, and BM mature and immature eosinophils were determined by nuclear morphology, www.selleckchem.com/products/PD-0332991.html cell size and cytoplasmic granulation.23 Lung tissue cells.  The pulmonary circulation was perfused with ice-cold PBS and lungs were removed from the thoracic cavity. The lung tissue was thinly sliced and suspended

RPMI-1640 (Sigma-Aldrich) complemented with 10% fetal calf serum (FCS), collagenase (5·25 mg/ml) and DNAse (3 mg/ml; Roche). After 90 min incubation in a shaking water bath (37°), any remaining intact tissue was disrupted by repeated passage through a wide-bore Pasteur pipette and filtered through a 40-μm nylon mesh (BD Biosciences, Erembodegem, Belgium). The parenchyma lung cells were diluted in Percoll (density 1·03 g/ml; Amersham Bioscience, Uppsala, Sweden) and layered on a discontinuous gradient,

centrifuged at 400 g for 20 min. The cells in the top layer, mainly macrophages, dead cells and debris, were discarded. Cells at the Percoll interfaces were collected and washed in PBS complemented with 10% FCS. Total cell numbers were determined using standard haematological procedures. Antibodies.  Fluorescein isothiocyanate (FITC) -labelled anti-mouse CD34 (clone RAM 34; BD Bioscience), phycoerythrin (PE) or FITC-labelled anti-mouse CCR3 (clone 83101; R&D systems, 4-Aminobutyrate aminotransferase Abington, UK), biotinylated anti-mouse stem cell antigen-1 (Sca-1)/Ly6 (clone 177228; R&D Systems) followed by peridinin chlorophyll protein (PerCP) -labelled streptavidin, PE-labelled anti-mouse IL-5Rα (Clone 558488; BD Bioscience), PercP-labelled anti-mouse CD45 (clone 557235; BD Bioscience), FITC-labelled BrdU (BD Bioscience) and rabbit anti-mouse major basic protein (MBP) polyclonal antibody in combination with goat anti-rabbit PE or with biotinylated swine anti-rabbit followed by streptavidin-FITC were used. Animals were sensitized and exposed to OVA or PBS as described above.

The Vu domain might interact with MDA5. By this interaction, it was expected that oligomerization through the helicase domain of MDA5 was inhibited as shown in the V protein in PIV5 (30). However, the reason that this did not happen in the SeV V-R320G mutant was not known. Paramyxovirus V proteins, including the SeV V protein, have been shown to interact with MDA5 and inhibit downstream IFN-β production (19, 20, 28, 31). Inhibition of IFN-β production by the SeV V protein has also been shown to be Vu region-dependent (20). On the other hand, SeV infection has been shown to be sensed by RIG-I, a helicase with a CARD domain structurally similar

to MDA5, but not by MDA5, in cultured cells (32, 33, 34) and in gene knockout mice (35). However, involvement of MDA5 in induction

of innate immunity in SeV infection has also selleck products been suggested by a study on infection of MDA5-knockout mice with SeV (36), and by a study on an MDA5-specific inhibitory factor, dihydroxyacetone kinase (37). It has also been reported that both RIG-I and MDA5 are involved in inducing IFN-α/β in the case of measles virus infection in human cultured cells (38). The MDA5 and V interaction may be important for inactivation of IRF3 and SeV pathogenesis. The present work showed that mutant V proteins inhibited the MDA5 function see more in ways corresponding to viral pathogenicity. This suggests the importance of MDA5 inhibition by the V protein in mouse infection with SeV and further suggests involvement of MDA5 in innate immunity in SeV infection in mice. Significance of the interaction of the V protein with RIG-I, IKKɛ or IRF3 detected in this work remains to be determined. We thank Dr Tetsuya Yoshida (Hiroshima Rucaparib mw International University, Japan) for valuable discussions. We also thank Dr Atsushi Kato (National Institute for Infectious Disease, Japan) for providing anti-Vu antibody, Dr Steve Goodbourn (University of London, UK) for providing MDA5 cDNA, Dr Taro Kawai and Dr Shizuo Akira (Osaka University, Japan) for providing IPS-1 cDNA, and

Dr Takashi Fujita (Kyoto University, Japan) for providing the p-55C1B reporter plasmid. We also thank the staff of the Research Center for Molecular Medicine and the Analysis Center of Life Science, Hiroshima University for the use of their facilities. “
“We aimed to analyse granulysin (GNLY)-mediated cytotoxicity in the peripheral blood of patients with non-ST-segment elevation myocardial infarction (NSTEMI) treated with anti-ischaemic drug therapy. Thirty-nine NSTEMI patients with a median age of 70 years and 28 age-matched healthy subjects were enrolled in this study. On day 7 after MI, the number of GNLY+ lymphocytes in the peripheral blood increased approximately six-fold of that in the healthy subjects, measured by flow cytometry. On day 14, the number of GNLY+ cells significantly decreased in T, NKT, and both CD56+dim and CD56+bright NK subsets.

Another is to determine what DC learn from

their close interaction with the so-called fibroblastic reticular cells in the stroma of lymphoid tissues. Stromal cells are likely to be distinct in different regions of the lymph node where B cells, T cells and macrophages are enriched. A third challenge, also emphasized in Germain’s laboratory, is how DC orchestrate the interaction of two rare cells, the antigen-specific helper CD4+ T cells and killer CD8+ T cells. The medical impact of the last mentioned interaction of antigen-specific CD4+ and CD8+ T cells is notable. “Helped” CD8+ T cells mobilize better to infection challenge sites Epigenetic Reader Domain inhibitor 52, and are a goal for more effective T-cell-based vaccines in the future 53. An obstacle in vivo is to be able to do more imaging of DC in large

animals and humans, e.g. appropriately labeled, DC-targeting antibodies might be visualized by positron emission tomography (PET scanning). The tolerance field has been energized by exceptional progress with Foxp3+Treg as suppressors of immune responses. Rescigno’s Viewpoint54 addresses the valuable DC part of check details the equation. DC exert significant controls on Treg and, reciprocally, will likely be necessary in understanding how Treg work. During homeostasis, DC regulate the numbers of Treg 21, and when DC present specific antigens, they can expand antigen-specific Treg 55–58. Control of Treg seems to be carried out best by particular DC subsets such as the CD103+ DC (also marked by DEC-205/CD205, Langerin/CD207, occasionally CD8) 59–61. A challenge in going forward will be to learn how to control Treg in an antigen-specific manner. Until now, most research on Treg has involved approaches to totally remove them and then observe the rapid development

of various forms of autoimmunity and chronic inflammatory bowel disease 62. These valuable approaches document the essential role of Treg in suppressing autoinflammatory diseases and have revealed critical mechanisms. A major gap remains: to determine whether one can expand antigen-specific Treg and selectively Janus kinase (JAK) suppress unwanted immune responses. Early papers on antigen-specific Treg have involved TCR transgenic T cells. DC either expand transgenic natural Treg in the presence of IL-2 or induce adaptive Treg along with TGF-β 63–65. When DC generate natural and induced Treg specific for a single pancreatic islet autoantigen, the Treg suppress autoimmune diabetes, which involves multiple autoantigens 63–65. A clinically relevant goal now is to find out whether antigen-capturing DC expand specific Treg from the polyclonal repertoire. If we could learn to expand antigen-specific Treg, as Rescigno 54 emphasizes in her Viewpoint, we could achieve an entirely new approach to suppress allergy, autoimmunity and transplant rejection.

10 Rag2−/−) are adoptively transferred into lymphopenic hosts that express their cognate antigen, chicken ovalbumin, as a soluble protein in the bloodstream (sOva Rag2−/−). The combination of antigen and lymphopenia results in massive donor T-cell expansion, leading to multiorgan infiltration and lethal autoimmune disease mediated by Th1- and Th17-type effector T cells [14]. To determine whether Th2-type cytokines also play a role in this pathology, we selleck kinase inhibitor performed adoptive transfers and measured IL-4 and IL-13 by intracellular flow cytometry. These studies showed that, while unable to produce IL-4, a large fraction

of the donor T cells could produce IL-13 both during the onset (day 3) and peak (day 7) of disease. Many donor T cells were positive for IFN-γ and IL-17, which is consistent with previous work [14, 15], and few were positive for IL-2 (Fig. 1A). Having established that donor T cells produce IL-13 in sOva Rag2−/− SCH727965 hosts, we next asked whether they coexpress other cytokines. Surprisingly, we found that IL-13 often segregated with IFN-γ and IL-17 (Fig. 1B), the signature cytokines of Th1- and Th17-type effectors

[2, 6]. To ask whether IL-13-producing Th1 and Th17 cells can be generated in the absence of lymphopenia or systemic inflammation, we transferred DO11.10 Rag2−/− T cells into congenic, lymphoreplete mice, then immunized with Ova-pulsed antigen presenting cells (APCs). In contrast to sOva Rag2−/− hosts, we could detect donor T cells expressing both IL-4 and IL-13 in these immunized hosts, which demonstrates that our immunization protocol does induce “classical” Racecadotril Th2-type effectors. We could also detect IL-13+ donor T cells coexpressing either IFN-γ or IL-17, which confirms that IL-13-producing Th1 and Th17 cells can be generated in the context of

“protective” immune responses. In fact, on a per cell basis, the percentage of Th1 and Th17 cells producing IL-13 was comparable between immunized and autoimmune sOva Rag2−/− hosts (Fig. 1C and D). It should also be noted that, overall, the percentage of IL-13+ cells was far greater than that of IL-4+, IFN-g+, or IL-17+ cells, which suggests that IL-13 can be produced either alone or in concert with unidentified cytokines. Coexpression of IFN-γ and IL-17 was seen in sOva Rag2−/− hosts but not immunized hosts, which suggests a link to autoimmunity, and coexpression of IL-17A and IL-17F was common to both models (Supporting Information Fig. 2). To ask whether IL-13-producing Th1 and Th17 cells can be generated during polyclonal T-cell responses, we used a model of chemically induced colitis where T cells are primed in response to a range of microbial and self-antigens. First, we determined that, compared to untreated controls, DSS-treated mice had increased numbers of IL-13+ CD4+ TCRβ+ cells within mesenteric lymph nodes (Supporting Information Fig. 3).

[16, 17, 25] Clearly new therapeutic strategies are required for this deadly disease. Such potential novel therapies can be better designed with comprehensive understanding of the mechanism of infection and its related host defence. Iron uptake from the host by

microorganisms is essential for the establishment and progression of infection since this element is required for the survival of living cells.[26] In a normal host, free iron is restricted by highly efficient iron sequesters such as transferrin, ferritin and lactoferrin.[26] Pathogens either devise strategies to obtain iron from the host by stripping iron from these sequesters (e.g. by siderophore production), or the tightly controlled free iron becomes more available in certain medical conditions. The unique susceptibility of certain patient populations to mucormycosis, but not to other pathogenic buy H 89 fungi, point to the importance of iron uptake in the pathogenesis of mucormycosis.[3, 23] These include, hyperglycaemic, DKA and other forms of Rucaparib chemical structure acidosis patients as well as deferoxamine-treated patients. All these patient categories suffer from elevated available serum iron. For example, the excessive glycosylation of proteins such as transferrin and ferritin, due to constant hyperglycaemia result in decreased iron affinity of these sequesters

which leads to the release of free ion in the blood stream and in cells.[27] Similarly, DKA and other forms of acidosis cause proton-mediated dissociation of iron from iron-sequestering proteins.[28] The increased levels of available iron enable enhanced growth of Mucorales in serum.[9, 28, 29] It is also known that DKA mice are more susceptible to mucormycosis infection than normal mice and iron chelation therapy using deferiprone or deferasirox protects DKA mice from mucormycosis.[29, 30] Subsequent studies confirmed the efficacy of deferasirox in treating experimental mucormycosis using the Drosophila fly model.[31] Patients with iron overload toxicity were used medroxyprogesterone to be treated with the bacterial iron-siderophore, deferoxamine.

These patients were found to be extremely susceptible to deadly form of mucormycosis.[32-34] Subsequent studies demonstrated that although deferoxamine is an iron chelator from the perspective of the human host, Rhizopus spp. utilise ferrioxamine (the iron-rich form of deferoxamine) as a xeno-siderophore to obtain previously unavailable iron.[35, 36] It was found that ferrioxamine binds to a cell surface receptor on the surface of Rhizopus and through an energy dependent reductive step releases ferrous iron prior to transporting it across the fungal cell membrane without deferoxamine internalisation.[36] Subsequent studies demonstrated that reduction in the high-affinity iron permease FTR1 copies (Mucorales are multinucleated organisms) in R.

Masuda [22] demonstrated that there was a significant correlation between the RORγt mRNA levels and the Th1/Th2 ratio in CD4+ cells, but they did not find any significant correlation between the frequency of Th17 cells (%) in the peripheral lymphocytes and the clinical QMG scores (%). In our study, a further regression analysis Metabolism inhibition showed that

the frequency of Th17 cells (%) and the QMG score had a significant positive correlation in MG patients with TM. However, we did not find any similar correlation in TH group or NT group. In this regard, these results indicated that the frequency of Th17 cells (%) was correlated with MG severity only in TM. The balance of Th17 cells and Treg cells was suggested to be responsible for many autoimmune diseases including primary biliary cirrhosis, allergic asthma and systemic lupus erythematosus [32–34], and many studies have also

suggested an important role of Treg in the pathogenesis of MG. Luther [10] found a marked decrease in the number of CD4+ CD25+ Treg cells in MG-associated TM, but no differences in the peripheral blood. In addition, Balandina [9] found a severe suppressive activity impairment of thymic CD4+ CD25− FoxP3+ Treg cells in patients with MG. In our previous study [35], we found that the Treg cell counts in TM accompanying MG were significantly lower than those in normal thymuses. Among the thymoma types, type B1 thymoma had the highest Foxp3+ nTreg count and standard values of Foxp3 mRNA. Further, in this study, we found that the proportion of CD4+ FoxP3+

Treg cells in the peripheral blood from TM group was significantly lower than those from TH group, NT group and FK228 HC group. Thus, our results suggest that the percentage of CD4+ FoxP3+ Treg cells both in the peripheral lymphocytes and in the thymus also contributes to the pathogenesis of MG with TM. However, the role of Th17 cells in TM in the pathogenesis and progression of MG needs further study. In conclusion, Th17 cells and Treg cells play a key role in immune regulation, and the Th17/Treg imbalance in TM may result in the destruction of immune tolerance and Molecular motor induce autoimmune disorders, such as MG. Our results indicated that the transcriptional levels of IL-17 and numbers of Th17 cells increased significantly in patients with MG accompanying TM. In addition, we demonstrated a positive relationship between the frequency of Th17 cells (%) and the concentration of AChR antibodies in serum. The increased IL-17 levels in this circumstance may promote the autoreactivity of T cells as well as B cells, and the activated T and B cells may then influence the production of self-reactive antibodies and aggravate the disease. Our findings suggest that Th17 cells and their related cytokines are involved in the pathophysiological process of MG, especially in MG with TM. The underlining mechanisms, and the diagnostic value and therapeutic indication of Th17 cells and their related cytokines in MG need further evaluation.

In particular, sirolimus dramatically suppressed oedema, reduced leucocyte infiltration and maintained mucosal integrity in TNBS-treated mice. These results apparently provide evidence of the therapeutic effect of sirolimus on experimental colitis and indicate that inhibition of the activity of mTOR is able to decrease the production of pro-inflammatory cytokines and disease parameters, thereby turning off the immune response APO866 datasheet of TNBS-induced experimental colitis. In conclusion, the present study shows that pre-treatment with sirolimus, the inhibitor of

mTOR, alleviated the perpetuation of TNBS-induced colitis. This amelioration was paralleled by promoting differentiation of Treg cells and inhibiting the generation of Th17 cells. Sirolimus treatment resulted in a significant histological improvement, protecting against mucosal ulcerations. This study suggests that sirolimus-based pharmaceutical strategies may offer a promising alternative to our current approaches of managing IBD. The project was supported by Guangdong Natural Science Foundation

(Grant S2012010009409) and the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry Selleck Veliparib [No (2011)1139]. The authors declare no conflict of interest. “
“We show that the T-cell immunoglobalin mucin, Tim-1, initially reported to be expressed on CD4+ T cells, is constitutively expressed on dendritic cells (DCs) and that its expression further increases after DC maturation. Tim-1 signaling into DCs upregulates costimulatory molecule expression and proinflammatory cytokine production, thereby promoting effector T-cell responses, while inhibiting Foxp3+ Treg responses. By contrast, Tim-1 signaling in T cells only regulates Th2 responses. Using a high-avidity/agonistic anti-Tim-1 antibody as a co-adjuvant enhances the immunogenic function of DCs, decreases the suppressive function of Tregs, and substantially increases proinflammatory Th17 responses in Orotic acid vivo. The treatment with high- but not low-avidity anti-Tim-1 not only worsens experimental autoimmune encephalomyelitis

(EAE) in susceptible mice but also breaks tolerance and induces EAE in a genetically resistant strain of mice. These findings indicate that Tim-1 has an important role in regulating DC function and thus shifts the balance between effector and regulatory T cells towards an enhanced immune response. By understanding the mechanisms by which Tim-1 regulates DC and T-cell responses, we may clarify the potential utility of Tim-1 as a target of therapy against autoimmunity, cancer, and infectious diseases. The T-cell immunoglobulin mucin (Tim) family of proteins are expressed on various immune cells and regulate immune responses 1–3. Tim-1 was first identified as a hepatitis A virus cellular receptor 1 (HAVCR1) 4, 5 and later as a kidney injury molecule, KIM-1 6, 7.

51,53 SEVI significantly enhances binding of wild-type HIV-1 particles and virions lacking Env, although the absolute levels of CA p24 are about 30-fold lower in the absence of Env.48 SEVI

enhances in vitro HIV infection in a dose- and time-dependent manner, and its effects are seen across different envelopes.54 Infection enhancement, however, appears to be donor dependent.54 Further experiments showed that SEVI enhanced infection with R5-, X4- and dual-tropic HIV-1 clones. Importantly, the enhancing effect of SEVI was most pronounced at low concentrations of virus, resembling conditions of sexual HIV-1 transmission.48 In general, these authors stated that SEVI may promote virus attachment to genital surfaces, penetration of the mucosal barrier, and subsequent dissemination to lymphoid organs by increasing Navitoclax manufacturer HIV-1 virion binding to epithelial cells and to migrating DCs.48 This

is in accordance with confocal microscopy data that shows the presence of seminal fluid enhances binding of virions to epithelial BMN-673 cells in ex vivo CV tissue.55 Using dose/response assays, it was determined that 1–3 virions, in the presence of SEVI, are sufficient for productive HIV-1 infection of PBMCs.48 The effect of SEVI enhancement was tested in hCD4/hCCR5-transgenic rats inoculated with either HIV-1 YU2 or SEVI-treated HIV-1.48 Tail vein inoculation with SEVI-treated HIV-1 increased the cDNA copy numbers in splenectomy extracts by fivefold.48 Further testing of SEVI in animal models is warranted, as reproducibility of the enhancing effect in vitro varies according selleck screening library to the laboratory and assay conditions employed, casting doubts about the relevance of this phenomenon. Another possible enhancing effect of semen is mediated by electrostatic interaction of spermatozoa with HIV-1 virions, involving negatively charged heparin sulfate. This complex can transmit virus directly to DC-SIGN on DCs.56 Once the spermatozoa are internalized by DCs, the DCs undergo phenotypic maturation and produce IL-10.56 Other receptors on spermatozoa may also be involved. Roan et al.51 hypothesized that SEVI, because

of its highly cationic nature, may bind to target cells by interacting with cell-surface heparan sulfate proteoglycans (HSPG), naturally occurring anionic carbohydrate polymers that are closely related in structure to heparin sulfate. They hypothesized that HSPG antagonists would inhibit the viral enhancing effects of SEVI.51 Surfen, a HSPG antagonist, induced a dose-dependent inhibition of SEVI at concentrations of 6.25 μm with the maximal inhibitory plateau occurring at 50–100 μm.57 Surfen appeared to directly inhibit SEVI and not compromise the infectivity of the virions.57 Electrostatic interactions between SP and microbicides may also hamper the efficacy of HIV-1 prevention products. The antiviral activity of several anionic polymer microbicide candidates (e.g.