Using mice that express an internalization defective S1P1, created by mutation of five C-terminal serine residues to alanine (S1P1S5A),[20] we demonstrated that this altered S1P1 resulted in the development of substantially worse EAE pathology.[54] These mice also had enhanced Th17 polarization with significantly increased production of both IL-6 and IL-17. This manifested as more severe neuroinflammation and a significant increase in central nervous system-infiltrating Th17 cells (Fig. 1c). Since S1P1 was reported to impact STAT3 signalling, we hypothesized that the observed increase in Th17 cells was due to potentiation of STAT3 signalling. Indeed, even at resting

state, these cells displayed increased phosphorylation of STAT3, and inhibiting BMS 907351 Afatinib concentration STAT3 signalling or Jak activation resulted in diminished IL-17 production. Other models where S1P1 was transgenically over-expressed in T cells were consistent with increased Th17 activation.[55] Adding S1P to Th17 polarizing cultures also assisted in Th17 induction[56] to an extent similar to IL-23 supplementation. Dynamic interactions between S1P1 trafficking roles and effector cell polarization activities have not been investigated, and connection of these two processes could add to the model of how T cells integrate information from their surroundings and make phenotype decisions. Our focus so far has centred on the trafficking

patterns of naive T cells and subset differentiation affected by S1P1; however, memory T cells may also be influenced by S1P1 signalling (Fig. 1d). Memory T cells are considered to be ‘antigen-experienced’, because they have been activated by a previous encounter with their cognate antigen, and survive after the primary immune response to be mobilized in the case of re-exposure or re-infection. These memory cells can be further subdivided into T central

memory (Tcm) and T effector memory (Tem) subsets.[57] The Tcm cells retain expression of Adenosine the lymph node homing receptors CCR7 and CD62L, whereas Tem cells do not express CCR7 and can migrate into tissues and respond to inflammatory chemokines. Clinical studies using the drug FTY720 demonstrated that modulation of S1P signalling could reduce both naive and Tcm cells in circulating blood and enrich for the CCR7− Tem cells, presumably because the principal egress signal is blocked, whereas the ability to home to lymph nodes is maintained in naive and Tcm cells.[58] Previous studies established the importance of Th17 cells in EAE, but there is strong evidence that memory T cells also have roles in multiple sclerosis pathology.[59, 60] Treatment with FTY720 reduced the frequency of IL-17-producing T cells in the blood of patients, which led to the hypothesis that Tcm cells were the primary precursors of Th17 cells in multiple sclerosis.

ALOX5AP itself lacks enzymatic activity and instead serves to enhance 5-lipoxygenase (LO) activity [9]. In the first step of the 5-LO pathway, 5-LO, in co-operation with ALOX5AP, converts arachidonic acid to leukotriene (LT) A4 (LTA4). Subsequently, LTA4 can be converted to LTB4 by LTA4 hydrolase and/or converted to LTC4 by LTC4 synthase; LTC4 is then cleaved into LTD4 and LTE4 [10]. The products of the

5-LO pathway, including LTC4, LTD4, LTE4 and LTB4, are known to play an important roles in allergic diseases such as asthma, allergic rhinitis and atopic dermatitis [11]. Many studies have analysed the genes in the 5-LO pathway for possible associations with asthma-susceptibility. For example, Choi et al.

[12] found that the ALOX5-[G-C-G-A] haplotype influences the development Tamoxifen cost of aspirin-intolerant asthma in a Korean population. The same study also showed that leukotrienes may play a role in the pathophysiology of asthma in a Korean population. Moreover, it has been reported that patients with asthma express ALOX5AP at higher levels than the general population [13]. Another study has shown that ALOX5AP promotes asthma either on its own and/or via its interactions with genes in the click here leukotriene pathway [14]. In addition, ALOX5AP has been reported to play a critical role in the pathogenesis of various cardiovascular diseases [15, 16]. Therefore, inhibitors of ALOX5AP are likely to be clinical beneficial in allergic asthma and various cardiovascular diseases [17]. However, although it has been proposed that ALOX5AP may play a potentially causative role in asthma, its relationship with lung Cobimetinib clinical trial function in a general population has not yet been examined [18]. In this study, the influence of genetic variation in the ALOX5AP gene on the lung functions of a healthy and general population was evaluated. Subjects.  The data used in this study were obtained from the Korea Association Resource (KARE) project in the Korean

Genome Epidemiology Study (KoGES), which began in 2001, was conducted by the Korea National Institute of Health (KNIH) [19]. The KoGES study was a cross-sectional analysis of 5018 and 5020 subjects from urban (Ansan) and rural (Ansung) communities in Korea, respectively. The ages of the participants ranged from 40 to 69 years. After a quality control process had been implemented, 8842 subjects in total were selected. General characteristics (age, sex, area, height, etc.), smoking status, medical history and current medications were collected from participants by questionnaires and the assessments were managed by trained interviewer. The participants have been examined every 2 years and 6-year follow-up study was currently completed. The procedures were conducted according to institutional guidelines and approved by an institutional review committee.

One hundred micro litres of peripheral blood (EDTA) was incubated for 20 min in the dark with monoclonal antibodies against CD4 (FITC), CD127 (PE), CD25 (APC), CD 3 (PerCP) (all Becton Dickinson, Heidelberg, Germany).

Red cells and platelets were lysed (Lysing solution, Becton Dickinson); the remaining mononuclear cells were analysed by flow cytometry (FACs Calibur™; Becton Dickinson) according to standard laboratory guidelines. Each measurement included 50,000 events in the gate of lymphocytes. The numbers of each measured cell population are expressed as per cent of circulating CD3+ T cells if not indicated otherwise. Tregs were characterized as CD4+CD25+CD127low cells. Figure 1 shows a representative FACS analysis. In a second experiment to quantify Th17 cells, mononuclear cells were click here prepared by density gradient centrifugation (Polysucrose, Biocoll, Biochrom Apoptosis inhibitor AG, Berlin, Germany). Further preparing and staining with a cell activation mixture containing the phorbol ester, PMA (Phorbol 12-Myristate 13-Acetate) and a calcium ionophore (ionomycin) were performed according to the manufacturer’s guidelines (Leukocyte Activation Cocktail, CD3 (FITC),

CD4 (PE), IL-17 (APC), all Becton Dickinson, Heidelberg, Germany). The numbers of each measured cell population are expressed as per cent of circulating CD3+ T cells if not indicated otherwise.

Th17 cells were characterized as CD3+CD4+IL17+ cells. Data are expressed as mean + SEM, if not indicated otherwise. Differences in T cell counts between PR-171 order the groups were examined by student’s t-test; differences in course of time were examined by anova followed by Bonferroni post hoc test. Statistical significance was assumed at P < 0.05. Twelve of 18 patients (67%) with iDCM who underwent IA therapy showed an improvement of left ventricular systolic function (defined as an increase in EF > 5%) at 6-month follow-up as compared to the corresponding values before IA. These patients were defined as ‘IA responder’. In 6 patients, left ventricular ejection fraction remained almost unchanged during a 6-month observation period (Δ EF ≤ 5%): these patients were defined as ‘IA non-responder’. Table 1 summarizes the baseline characteristics and demographic data for the patients with iDCM (all, IA responder, IA non-responder) before and 6 months after IA therapy. For comparison, the data from 12 patients with chronic ischaemic cardiomyopathy and 5 patients with iDCM without IA at the time of inclusion and 6 months later were also given. Of note, left ventricular ejection fraction and enddiastolic diameter improved significantly in the IA responder group only. Not unexpected, left ventricular indices were unchanged in the control group (ischaemic heart failure).

Importantly, how commensals contribute to the expression

of these enzymes and metabolism of vitamin A remains unknown. Another important question is the timing necessary for DCs migrating in the GALT to acquire RA from epithelial cells and how these processes can be modified during infection. How RA contributes to oral tolerance, and at the same time protective immunity in the GI tract, also remains to be addressed. One possibility is that RA favours the induction of Tregs in the absence of secondary signals but enhances effector responses following exposure to inflammatory mediators. Treg populations require not only appropriate conditions for their induction, but also for their upkeep, particularly when confronted with an inflammatory environment. Very recently it has been shown that, in the gut, myeloid cell-derived IL-10 plays a crucial role in maintaining functional Treg activity by stimulating Compound Library IL-10R directly on FoxP3+ Tregs and allowing them to play a fully protective role in the prevention of colitis [45]. Thus, in the absence of either innate IL-10 production, or IL-10R on Tregs, these cells lose

the ability to block colitogenic effector T cells from causing inflammatory disease, and indeed succumb themselves to the inflammatory process by switching to the production of IFN-γ[45]. Hence, IL-10 is important for the maintenance of Treg activity and can be through pivotal at the tipping-point between regulation selleck chemicals and inflammation. The regulation of Treg activity between the gut and the periphery is also of special interest, as IBD in humans may affect extraintestinal organs in up to 36% of cases [46]. IBD-related extraintestinal disorders are not specific to IBD. They can be classified into reactive manifestations dependent directly upon intestinal disease. The often co-existing presentation in the same patient points towards common underlying pathomechanisms that may involve enteric flora activating the immune system to turn against bacterial antigens and, based

on cross-reactivity, against intestinal antigens and antigens in extraintestinal organs (‘molecular mimicry’). A separate subset of IBD patients shows an increased frequency of other common autoimmune diseases that manifest mainly independently of the bowel disease. This may thus reflect susceptibility to autoimmunity in general. The complex relationship between intestinal and extraintestinal manifestations in IBD is also reflected by the complex multi-genetic control reported in animal models of IBD; genetic loci regulating intestinal and extra-intestinal manifestations are largely but not exclusively different [47]. The appearance of GI parasites is a major challenge to the discriminatory powers of the immune system, and one which in evolutionary time has been played out countless times.

Compared to the increase in circumference or diameter (which ranges from 25 to 220% [13, 55, 39, 73, 12, 25, 38, 48, 57, 74, 75]) changes

in axial length may be on the order of 300–500%, at least in the rat [13]. This elongation is structural rather than elastic, because it was measured under unstressed conditions. Viewed from a more integrated, three-dimensional perspective that considers the change in circumference and length (most studies focus on only the former), the extent of hypertrophy becomes even more pronounced. In terms of uterine vascular resistance (and, therefore, effect on blood flow), arterial circumferential vs. axial changes oppose each other as increases in lumen diameter decrease, while increases in length increase resistance. According to Poiseiulle’s Law, Gefitinib chemical structure the relationship between lumen diameter and resistance is inverse and quadratic, while that of length to resistance buy SB203580 is proportional and linear. Hence, if a vessel doubles its diameter, it would have

to increase its length 16-fold to maintain the same blood flow resistance. Therefore, widening is a more powerful modulator of resistance and flow than lengthening. The internal milieu of pregnancy, which is characterized by high circulating levels of not only sex steroids but also of growth factors and other endocrine signals, may well stimulate uterine vascular remodeling. Studies of pseudopregnancy, in which mechanical stimulation leads to a pregnancy-like endocrine state in rodents, have shown that significant increases in uterine artery diameter do occur in mice during the first half of pregnancy, even without the presence of true implantation sites [82]. Maximal increases in arterial radius were observed on day 11, and were on the order

of 20–25%. This enlargement is significant but lags behind the 30–35% changes seen at the same time point in pregnant animals. Steroidal influences therefore likely contribute to arterial enlargement, especially during early- to mid-pregnancy. They may also augment the extent of the process through synergistic effects with other factors, such as shear Phosphatidylinositol diacylglycerol-lyase stress [77, 87] or VEGF [76], although additional research is needed to better define the interactive aspects in the gestational setting. In rats, if implantation is restricted to one uterine horn (rodents usually have two identical horns, making this an ideal experimental model), the majority of the remodeling occurs only in the “pregnant” horn [22], indicating that local rather than systemic factors are paramount. Parenthetically, rodents also maintain normal fecundity by increasing the number of implantation sites from 6 or 7 to 12–14, a number that is similar to that typically present in both horns in a control animal. The stark difference in the extent of remodeling in the implanted vs.

The activation of T cells is mediated through T cell receptors (TCR), and this activation can be modulated by killer immunoglobulin-like receptors (KIR) [3,4]. KIR are members of the immunoglobulin superfamily and are expressed on natural killer (NK)

cells and subsets of T cells. Depending on their structure, they can generate activating or inhibitory signals [5]. Inhibitory KIR molecules bind to target cell major histocompatibility complex (MHC) class I molecules and prevent the MI-503 order attack of NK cells on normal cells [5]. The capacity to attack self cells that lack expression of MHC class I molecules is known as ‘missing self recognition’[6,7]. The missing-self hypothesis has been supported by several independent findings demonstrating that allotypic MHC products actually protect cells from lysis by NK lymphocytes, apparently by delivering negative signals that inhibit NK cell cytotoxic

function [7]. On the other hand, when an activating KIR binds to its ligand, activating signals are generated leading to the kill of the target cells. Besides the modulation of TCR-mediated activation of T cells, KIR expression may affect the role Selleckchem RXDX-106 of NK cells in autoimmune diseases, where these cells may exert a pathogenic function through inappropriate activation or suppression function through lysis of dendritic cells or activated T cells [5]. Therefore, genes that control KIR expression may possibly influence normal and pathological immune responses. To date, 17 KIR genes and pseudogenes have been described on human chromosome 19q13.4 (∼0·7 Mb) [8]. Eight genes that encode KIR receptors are inhibitory (2DL1, 2DL2, 2DL3, 2DL5A, 2DL5B 3DL1, 3DL2 and 3DL3), seven are activating (2DL4, 2DS1, 2DS2, 2DS3, 2DS4, 2DS5, 2DS5 and 3DS1) and two are pseudogenes (2DP1 and 3DP1). Of these, four KIR genes are always present: 3DL3, 3DP1, 2DL4 and 3DL2. They are considered framework genes [9]. A previous study those by Momot et al.[10] suggested that the presence of KIR2DS2+, in the absence of KIR2DL2-, is associated with SSc. In contrast, Pellet

et al.[11] found association of the disease with the presence of KIR2DS1 and the absence of KIR2DS2. Given these contradictory results, we designed a study to investigate further the association of KIR genes with systemic sclerosis. One hundred and ten patients with systemic sclerosis were evaluated prospectively in the out-patient clinic of the Service of Rheumatology at the Hospital de Clínicas de Porto Alegre. All patients met the American College of Rheumatology (ACR) criteria for SSc [12] or the criteria suggested by LeRoy and Medsger for diagnosis of early forms of SSc [13]. All patients were Brazilian (92 women and 18 men; 81·8% European descendents and 18·2% African descendents) and most of them lived in the metropolitan area of Porto Alegre/RS. There were neither individuals of Asiatic origin nor Amerindians among the patients. Patients with overlapping syndromes were excluded.

Organ Procurement Organizations (OPO) partnering with nPOD to provide research resources are listed at http://www.jdrfnpod.org/our-partners.php. “
“Major histocompatibility complex (MHC) class II molecules present antigenic peptides derived from engulfed exogenous proteins to CD4+ T cells. Exogenous antigens are processed in mature endosomes and lysosomes where acidic proteases reside and peptide-binding to class II alleles is favoured. Hence, maintenance of the microenvironment within these organelles is probably central to efficient MHC class II-mediated antigen presentation. Lysosome-associated CH5424802 membrane

proteins such as LAMP-2 reside in mature endosomes Vadimezan clinical trial and lysosomes, yet their role in exogenous antigen presentation

pathways remains untested. In this study, human B cells lacking LAMP-2 were examined for changes in MHC class II-restricted antigen presentation. MHC class II presentation of exogenous antigen and peptides to CD4+ T cells was impaired in the LAMP-2-deficient B cells. Peptide-binding to MHC class II on LAMP-2-deficient B cells was reduced at physiological pH compared with wild-type cells. However, peptide-binding and class II-restricted antigen presentation were restored by incubation of LAMP-2-negative B cells at acidic pH, suggesting that efficient loading of exogenous epitopes by MHC class II molecules is dependent upon LAMP-2 expression in B cells. Interestingly, class II presentation of an epitope derived from an endogenous transmembrane protein was Urease detected using LAMP-2-deficient B cells. Consequently, LAMP-2 may control the repertoire of peptides displayed by MHC class II molecules on B cells and influence the balance between endogenous and exogenous antigen presentation. Major histocompatibility complex (MHC) class II molecules

present antigenic peptides derived from exogenous proteins to CD4+ T cells.1 These MHC class II proteins are constitutively expressed on the surface of a number of professional antigen-presenting cells (APC) such as dendritic cells, B cells and macrophages. The MHC class II complexes consist of α and β subunits which are first assembled in the endoplasmic reticulum with the chaperone molecule invariant chain (Ii).2,3 The cytoplasmic tail of Ii contains a motif that targets the Ii–MHC class II complexes to endosomal/lysosomal compartments. Here, acidic proteases degrade Ii to a small fragment known as class II-associated invariant chain peptide (CLIP), which remains associated with the MHC class II peptide-binding groove.4,5 Antigens delivered into the endosomal/lysosomal network via receptor-mediated or fluid-phase endocytosis are also exposed to proteases and denaturing reactions, yielding peptide ligands for class II molecules.

e. at an effector : target cell ratio of 1:1) and with or without 5 ng/ml of GM-CSF. In some experiments, eosinophils were preincubated for 30 min with anti-FcγRII and/or anti-CD18 (5 μg/ml). The plates were incubated for 2 hr at 37° in an atmosphere of 5% CO2. The cells were then collected from the wells, centrifuged in a Cytospin cytocentrifuge (Eppendorf AG, Hamburg, Germany) for 5 min and stained with May–Grünwald–Giemsa, and the number of eosinophils (out of a total of 100) containing ingested cryptococci was determined by counting no fewer than 500 cells. Three-hundred-thousand Fulvestrant research buy cells were plated on a 96-well U-shaped

plate with the same number of opsonized or non-opsonized yeast cells, or with medium alone, in the presence or absence of GM-CSF. In some experiments, the eosinophils were preincubated

for 30 min with anti-FcγRII and/or anti-CD18 (5 μg/ml). The plates were incubated at 37° and 5% CO2 for 24 hr. The cells were then blocked with anti-(rat FcγRII) (CD32) for 15 min at room temperature and stained with anti-(rat MHC class I), anti-(rat MHC class II), anti-(rat CD80) or anti-(rat CD86) for 30 min under the same conditions. After incubation, the cells were collected by centrifugation, fixed in 1% Paraphormaldehyde, washed three times with wash buffer and then 20 000 events were analyzed by flow cytometry (Cytoron Absolute; ORTHO Diagnostic System, Raritan, NJ). The percentage of positively labelled cells was determined using logarithmic-scale histograms. Autofluorescence was assessed using untreated cells and control isotypes. Cells were plated at a density of 106/ml in medium with or without GM-CSF (5 ng/ml), on a 24-well plate containing DMXAA 106 opsonized yeast cells/ml. In some experiments, eosinophils were preincubated for 30 min with anti-FcγRII and/or anti-CD18 (5 μg/ml). Nitrite accumulation, an indicator

of NO production, was measured using the Griess reagent.6 Briefly, 100-μl aliquots of 24-hr culture supernatants were mixed with an equal amount of Griess reagent and incubated at room temperature for 15 min. The absorbance at 540 nm was measured using an automated microplate reader Resminostat (BioRad, Hercules, CA). The concentration of nitrite was calculated from a NaNO2 standard curve. To measure the concentration of intracellular H2O2, eosinophils were incubated with DCF, with the non-fluorescent reduced form being converted into a green fluorescent form when oxidized. DCF is oxidized by cellular H2O2, hydroxyl radicals and other free-radical products of H2O2. However, it is relatively insensitive to oxidation by superoxide.26 Eosinophils were treated for 2 hr (because at earlier time-points there was no H2O2 release detected) in the presence or absence of GM-CSF (5 ng/ml), with medium alone or opsonized live yeasts, before being washed with PBS and treated with 10 μm DCF for 20 min at 37°. In some experiments, eosinophils were preincubated for 30 min with anti-FcγRII and/or anti-CD18 (5 μg/ml).

mexicana LPG relates with its success to infect murine macrophages. Leishmania parasites are the causal agents of Leishmaniasis, which is transmitted to mammals, including human beings, by phlebotomine sand flies. Selumetinib mouse Depending upon host immune response and parasite species, leishmaniasis is characterized by a wide spectrum of clinical manifestations. In Mexico, Leishmania mexicana is the causative agent of two forms of cutaneous leishmaniasis: localized cutaneous leishmaniasis (LCL), characterized

by ulcerative skin lesions that develop at the site of the bite of the sand fly, and diffuse cutaneous leishmaniasis (DCL), which consists of multiple nonulcerative nodules that spread throughout the skin, leading to severe mutilation CHIR-99021 because of the invasion of naso- and oropharyngeal mucosae. In murine models infected with L. mexicana, it has been shown that BALB/c mice are significantly more susceptible and develop larger dermal lesions as compared with C57BL/6 mice (1–3). In murine and human macrophages, it has been established that

the respiratory burst of the cell with generation of reactive oxygen intermediates (ROI), such as H2O2 and O2−, is largely responsible for parasite control, as these molecules have been reported to be fatal for Leishmania promastigotes (4–8). Another toxic molecule for the parasite is nitric oxide (NO), which is generated by macrophages stimulated by cytokines, such as TNF-α and IFN-γ (9,10). Respiratory burst activity and NO production are regulated by phosphorylation events mediated by protein kinase C (PKC), a family of serine/threonine kinases comprising at least 13 different members (11). The mammalian PKC superfamily is subdivided into three subfamilies on the basis of their structural differences and related cofactor requirements: cPKC (classical PKC) isoforms (α, βI, βII Dimethyl sulfoxide and γ), which respond both to Ca2+ and diacylglycerol (DAG); novel PKC (nPKC) isoforms (δ, ε, θ and η), which are insensitive to Ca2+, but dependent on DAG and atypical PKCs (aPKCs, ι/λ, ζ), which are nonresponsive to the co-factors, but may be activated by other lipids and

by protein–protein interactions. Macrophages and monocytic cells express the Ca2+-dependent and DAG-dependent isoenzymes α, βI, and βII, the Ca2+-independent isoenzymes δ and ε and the atypical isoenzyme ζ (12,13). Among the isoenzymes that are related to macrophage defence functions are PKCα, which has been shown to be the predominant isoenzyme required for the O2− production (14), whereas PKCβ is related to cell chemotaxis (15,16). It has been shown that PKCβ can be regulated by C-C chemokines (17). It has been reported that Leishmania donovani parasites, as well as Leishmania lipophosphoglycan (LPG), which is the most abundant glycoconjugate on the parasite surface, can impair signal transduction mediated by PKC in macrophages, thereby increasing intracellular survival of the parasites (18–21).

To generate the ChAdV68.GagB vaccine,

the HIV-1 consensus clade B Gag-derived Tg was inserted into the E1 region. In part confirming previous observations, the ChAdV68.GagB vaccine alone and in heterologous prime-boost regimens with plasmid DNA- and modified vaccinia virus Ankara (MVA)-vectored vaccines induced robust polyfunctional HIV-1-specific CD8+ and CD4+ T-cell responses with a gut-homing phenotype. Importantly, we showed that when a single epitope is expressed as an immunodominant CD8+ T-cell determinant, responses elicited by ChAdV68.GagB alone and in combination lowered surrogate challenge EcoHIV/NDK (where EcoHIV is chimeric ecotropic HIV) virus load in mice both at the peak T-cell frequencies 2 selleck inhibitor weeks after vaccination and 16 weeks later indicating development of protective effector memory. These results

parallel the immunogenicity of similar vaccine regimens in macaques and an ongoing phase I/IIa trial in humans, and support further development of vaccines vectored by ChAdVs. Adenoviruses are the most immunogenic nonreplicating, priming vectors under development for subunit genetic vaccines against HIV-1, the causative agent of AIDS. However, vaccine carriers based on common human adenovirus (HAdV) serotypes such as HAdV-5 have several major disadvantages that were highlighted in the proof-of-concept phase IIb STEP study [1]. First, most people have high levels of pre-existing adenovirus-neutralizing antibodies,

which decrease vaccine uptake and dampen induction of Ridaforolimus immune responses specific for the Tg product [2, 3]. Therefore, either rare human serotypes [2, 4], chimeric [5] or various animal [6, 7] adenoviruses are being exploited for potential human use. Second, similarly to most nonreplicating vaccine vectors, replication-deficient adenoviruses are not sufficiently immunogenic as stand-alone vaccines [8]. A dramatic increase in the frequencies of vaccine-induced HIV-1-specific T cells over a single vaccine modality can be achieved by combining diverse attenuated subunit vaccines sharing the same immunogen gene into heterologous prime-boost regimens [9-11]. Assembling these regimens is mostly empirical, although some Dipeptidyl peptidase general rules for combining different vaccine modalities into more complex sequential applications are emerging. Third, a strong pre-existing immunity to HAdV-5 correlated in one specific subpopulation (uncircumcised men) with a moderate increase in HIV-1 acquisition following vaccination with recombinant HAdV-5 [12], although the underlying mechanism has not been firmly established. Whether this should be a real concern or not, HAdV-5 as a vector for HIV-1 vaccines is being replaced by alternative, in some cases at least equally immunogenic, adenoviruses [7] minimizing any such potential issues.