Immune modulation via dendritic cells by the effect of Thymosin-alpha-1 on immune synapse in HCMV infection.

Tα1 (Thymosin-alpha-1) is a thymus-derived hormone that has been demonstrated to be effective on diverse immune cell subsets. The objective of this study was to determine the in vitro immunomodulatory effect of Tα1 in human cytomegalovirus (HCMV) infection. Dendritic cells (DCs) were isolated from peripheral blood mononuclear cells (PBMCs) by negative selection and cultured in the presence or absence of Tα1. The immunophenotyping of DCs was characterised by multiparametric flow cytometry assessing CD40, CD80, TIM-3 and PDL-1 markers, as well as intracellular TNFα production. Then, autologous CD4+ or CD8+ T-Lymphocytes (TLs) isolated by negative selection from PBMCs were co-cultured with DCs previously treated with Tα1 in the presence or absence of HCMV. Intracellular TNFα, IFNγ, IL-2 production, CD40-L and PD-1 expression were assessed through immunophenotyping, and polyfunctionality in total TLs and memory subsets were evaluated. The results showed that Tα1 increased CD40, CD80, TIM-3 and TNFα intracellular production while decreasing PDL-1 expression, particularly on plasmacytoid dendritic cells (pDCs). Therefore, Tα1 modulated the production of TNFα, IFNγ and IL-2 in both total and memory subsets of CD4+ and CD8+ TLs by upregulating CD40/CD40-L and downregulating PDL-1/PD-1 expression. Our study concludes that Tα1 enhances antigen-presenting capacity of DCs, improves TLs responses to HCMV infection, and enhances the polyfunctionality of CD8+ TLs. Consequently, Tα1 could be an alternative adjuvant for use in therapeutic cell therapy for immunocompromised patients.

The use of alpha 1 thymosin as an immunomodulator of the response against SARS-Cov2.

BACKGROUND: Since the beginning of SARS-CoV2 pandemic, the mortality rate among elderly patients (60-90 years) has been around 50%, so age has been a determining factor of a worse COVID-19 prognosis. Associated with age, the thymic function involution and depletion plays an important role, that could be related to a dysregulated and ineffective innate and adaptive immune response against SARS-CoV2. Our study aims to further in vitro effect of human Thymosin-alpha-1 (α1Thy) treatment on the immune system in population groups with different thymic function levels in the scenario of SARS-CoV2 infection. RESULTS: Activation markers such as CD40, CD80 and TIM-3 were upregulated in α1Thy presence, especially in plasmacytoid dendritic cells (pDCs) and, with increased TNFα production was observed compared to untreated condition. Co-cultures of CD4 + and CD8 + T cells with DCs treated with α1Thy in response to SARS-CoV2 peptides showed a decrease in the cytokine production compared to the condition without α1Thy pre-treated. A decrease in CD40L activation co-receptor expression in CD8 + LTs was also observed, as well as an increase in PD1 in CD4 + TLs expression in both age groups. In fact, there are no age-related differences in the immunomodulatory effect of the hormone, and it seems that effector memory and terminally differentiated memory T lymphocyte subsets were the most actively influenced by the immunomodulatory α1Thy effect. Finally, the polyfunctionality measured in SARS-CoV2 Specific-T cells response was maintained in α1Thy presence in total and memory subpopulations CD4 + and CD8 + T-cells, despite decreased proinflammatory cytokines production. CONCLUSION: The hormone α1Thy could reduce, through the modulation of DCs, the amount of proinflammatory cytokines produced by T cells. Moreover, α1Thy improve lymphocyte functionality and could become a beneficial therapeutic alternative as an adjuvant in SARS-CoV2 treatment either in the acute phase after infection or reinfection. In addition, the effect on the T immune response means that α1Thy can be incorporated into the vaccination regimen, especially in the most immunologically vulnerable individuals such as the elderly. SUBJECTS: Thymosin alpha 1, Dendritic cells, SARS-CoV2-specific T cells response, Immunomodulation.

Vaginal neutrophil infiltration is contingent on ovarian cycle phase and independent of pathogen infection.

The mucosa of the female reproductive tract must reconcile the presence of commensal microbiota and the transit of exogenous spermatozoa with the elimination of sexually transmitted pathogens. In the vagina, neutrophils are the principal cellular arm of innate immunity and constitute the first line of protection in response to infections or injury. Neutrophils are absent from the vaginal lumen during the ovulatory phase, probably to allow sperm to fertilize; however, the mechanisms that regulate neutrophil influx to the vagina in response to aggressions remain controversial. We have used mouse inseminations and infections of Neisseria gonorrhoeae, Candida albicans, Trichomonas vaginalis, and HSV-2 models. We demonstrate that neutrophil infiltration of the vaginal mucosa is distinctively contingent on the ovarian cycle phase and independent of the sperm and pathogen challenge, probably to prevent sperm from being attacked by neutrophils. Neutrophils extravasation is a multi-step cascade of events, which includes their adhesion through selectins (E, P and L) and integrins of the endothelial cells. We have discovered that cervical endothelial cells expressed selectin-E (SELE, CD62E) to favor neutrophils recruitment and estradiol down-regulated SELE expression during ovulation, which impaired neutrophil transendothelial migration and orchestrated sperm tolerance. Progesterone up-regulated SELE to restore surveillance after ovulation.

Safety and efficacy of G2-S16 dendrimer as microbicide in healthy human vaginal tissue explants.

BACKGROUND: The absence of an effective treatment and vaccine in HIV-1 pandemic place preventive strategies such as safety and effective microbicide development as a central therapeutic approach to control HIV-1 pandemic nowadays. RESULTS: Studies of cytotoxicity, immune population status, inflammation or tissue damage and mainly prophylactic inhibition of HIV-1 infection in vaginal human explants demonstrate the biosafety and effectivity of G2-S16 dendrimer. Human explants treated with G2-S16 dendrimer or treated and HIV-1 infected do not presented signs of irritation, inflammation, immune activation or T cell populations deregulation. CONCLUSIONS: Herein we conclude that G2-S16 dendrimer has demonstrated sufficient efficacy, biosafety, effectivity and behavior in the closest to the real-life condition model represented by the human healthy donor vaginal tissue explants, to raise G2-S16 dendrimer as a promising candidate to clinical trials to develop an effective microbicide against HIV-1 infection.

Promising PEGylated cationic dendrimers for delivery of miRNAs as a possible therapy against HIV-1 infection.

BACKGROUND: The appearance of resistance against new treatments and the fact that HIV-1 can infect various cell types and develop reservoirs and sanctuaries makes it necessary to develop new therapeutic approaches to overcome those failures. RESULTS: Studies of cytotoxicity, genotoxicity, complexes formation, stability, resistance, release and particle size distribution confirmed that G2-SN15-PEG, G3-SN31-PEG, G2-SN15-PEG-FITC and G3-SN31-PEG-FITC dendrimers can form complexes with miRNAs being biocompatible, stable and conferring protection to these nucleic acids. Confocal microscopy and flow cytometry showed effective delivery of these four dendrimers into the target cells, confirming their applicability as delivery systems. Dendriplexes formed with the dendrimers and miRNAs significantly inhibited HIV-1 infection in PBMCs. CONCLUSIONS: These dendrimers are efficient delivery systems for miRNAs and they specifically and significantly improved the anti-R5-HIV-1 activity of these RNA molecules.

Nanotechnology against human cytomegalovirus in vitro: polyanionic carbosilane dendrimers as antiviral agents.

BACKGROUND: Human cytomegalovirus (HCMV) is a worldwide infection, causing different troublesome in immunosupressed patients and very related to Human Immunodeficiency Virus 1 (HIV-1) infection, mainly in developing countries, with a co-infection rate of 80% in Africa. The high cost of present treatments and the lack of routinely tests in these countries urge the necessity to develop new molecules or strategies against HCMV. The new treatments should be low-cost and capable of avoiding the emerging problem of resistant virus. Nanoparticles play an important role in several viral infections. Our main focus is to study the potential activity of polyanionic carbosilane dendrimers (PDC), which are hyperbranched molecules with several sulfonate or sulfate groups in their periphery, against different viruses. RESULTS: We studied the activity of G1-S4, G2-S16 and G2-S24P PDCs in MRC-5 cell line against HCMV infection by several plaque reduction assays. Our results show that dendrimers present good biocompatibility at the concentrations tested (1-50 µM) for 6 days in cell culture. Interestingly, both G2-S16 and G2-S24P showed a remarked inhibition at 10 µM against HCMV infection. Results on attachment and virucidal assays indicated that the inhibition was not directed to the virus or the virus-cell attachment. However, results of time of addition, showed a longer lasting activity of these dendrimers in comparison to ganciclovir, and the combination of G2-S16 or G2-S24P with ganciclovir increases the HCMV inhibition around 90 %. CONCLUSIONS: Nanotechnology, in particular polyanionic carbosilane dendrimers, have proved their potential application against HCMV, being capable of inhibiting the infection by themselves or enhancing the activity of ganciclovir, the actual treatment. These compounds represent a low-cost approach to fight HCMV infections.

Increased CD127+ and decreased CD57+ T cell expression levels in HIV-infected patients on NRTI-sparing regimens.

BACKGROUND: NRTIs-sparing regimens exert favourable profiles on T-cell homeostasis associated parameters. Our aim was to analyze the effect of NRTIs sparing regimen (NRTI-sparing-cART) vs NRTIs-containing regimen (NRTI-cART), on T-cell homeostasis associated parameters in naive HIV-infected patients. METHODS: Biomarkers of cell survival (CD127) and replicative senescence (CD57), were measured by multiparametric flow cytometry for T-cell phenotyping on peripheral blood mononuclear cells (PBMCs) samples just before (baseline) and after 48 weeks of undetectable viral load in patients on NRTI-sparing-cART (N = 13) and NRTI-cART (N = 14). After 48 weeks a subgroup of patients (n = 5) on NRTI-cART switched to NRTI-sparing-cART for another additional 48 weeks. In vitro assays were performed on PBMCs from HIV-uninfected healthy donors exposed or not to HIV. To analyze the independent factors associated with type of cART bivariate and stepwise multivariate analysis were performed after adjusting for basal CD4+, CD8+ and nadir CD4+ T-cell counts. RESULTS: After 48 weeks of a NRTI-sparing-cART vs NRTI-cART patients have higher effector memory (EM) CD4+ CD127+ T-cell levels, lower EM CD4+ CD57+ T-cell levels, higher CD8+ CD127+ T-cell levels, lower CD8+ CD57+ T-cell levels and higher memory CD8+ T-cell levels. This effect was confirmed in the subgroup of patients who switched to NRTI-sparing-cART. In vitro assays confirmed that the deleterious effect of a NRTIs-containing regimen was due to NRTIs. CONCLUSIONS: The implementation of NRTI-sparing regimens, with a favourable profile in CD127 and CD57 T-cell expression, could benefit cART-patients. These results could have potential implications in a decrease in the number of Non-AIDS events.

Carbosilane dendrons with fatty acids at the core as a new potential microbicide against HSV-2/HIV-1 co-infection.

Herpes simplex virus type 2 (HSV-2) and human immunodeficiency virus type 1 (HIV-1) represent the two most frequent sexually transmitted infections (STI) worldwide. Epidemiological studies suggest that HSV-2 increases the risk of HIV-1 acquisition approximately 3-fold mainly due to the clinical and immunological manifestations. In the absence of vaccines against both STI, the development of new preventive strategies has become essential for further studies. We performed the screening of six novel polyanionic carbosilane dendrons to elucidate their potential activity against HSV-2/HIV-1 co-infection and their mechanism of action. These new nanoparticles are carbosilane branched dendrons from first to third generation, with palmitic or hexanoic fatty acids as the core and capped with sulfonate groups, named G1d-STE2Hx, G2d-STE4Hx, G3d-STE8Hx, G1d-STE2Pm, G2d-STE4Pm and G3d-STE8Pm. G3d-STE8Hx and G3d-STE8Pm carbosilane branched dendrons showed high viability. These dendrons also showed a great broad-spectrum antiviral activity, as well as a suitable efficacy against HIV-1 even if the mucosal disruption occurs as a consequence of HSV-2 infection. Our results exert high inhibition against HSV-2 and HIV-1 by blocking the entry of both viruses with the median effective concentration EC50 values in the nanomolar range. Additionally, G3d-STE8Hx and G3d-STE8Pm retained their anti-HSV-2/HIV-1 activity at different pH values. G3d-STE8Hx and G3d-STE8Pm dendrons may be potential candidates as dual-acting microbicides against HSV-2/HIV-1 co-infection.

Relationship between CCR5(WT/Δ32) heterozygosity and HIV-1 reservoir size in adolescents and young adults with perinatally acquired HIV-1 infection.

BACKGROUND: Several host factors contribute to human immunodeficiency virus (HIV) disease progression in the absence of combination antiretroviral therapy (cART). Among them, the CC-chemokine receptor 5 (CCR5) is known to be the main co-receptor used by HIV-1 to enter target cells during the early stages of an HIV-1 infection. OBJECTIVE: We evaluated the association of CCR5(WT/Δ32) heterozygosity with HIV-1 reservoir size, lymphocyte differentiation, activation and immunosenescence in adolescents and young adults with perinatally acquired HIV infection receiving cART. METHODS: CCR5 genotype was analysed in 242 patients with vertically transmitted HIV-1 infection from Paediatric Spanish AIDS Research Network Cohort (coRISpe). Proviral HIV-1 DNA was quantified by digital-droplet PCR, and T-cell phenotype was evaluated by flow cytometry in a subset of 24 patients (ten with CCR5(Δ32/WT) genotype and 14 with CCR5(WT/WT) genotype). RESULTS: Twenty-three patients were heterozygous for the Δ32 genotype but none was homozygous for the mutated CCR5 allele. We observed no difference in the HIV-1 reservoir size (455 and 578 copies of HIV-1 DNA per million CD4+ T cells in individuals with CCR5(WT/WT) and CCR5(Δ32/WT) genotypes, respectively; p 0.75) or in the immune activation markers between both genotype groups. However, we found that total HIV-1 DNA in CD4+ T cells correlated with the percentage of memory CD4+ T cells: a direct correlation in CCR5(WT/Δ32) patients but an inverse correlation in those with the CCR5(WT/WT) genotype. CONCLUSIONS: This finding suggests a differential distribution of the viral reservoir compartment in CCR5(WT/Δ32) patients with perinatal HIV infection, which is a characteristic that may affect the design of strategies for reservoir elimination.

Validation of the HIV Tropism Test TROCAI Using the Virological Response to a Short-Term Maraviroc Monotherapy Exposure.

TROCAI is a phenotypic tropism test developed using the virological response to a short-term exposure to maraviroc monotherapy (Maraviroc Clinical Test [MCT]). It was found that with TROCAI, a cutoff of <0.5% of dual/mixed viruses was needed to predict R5 HIV tropism. Here, we have validated TROCAI, using this cutoff, in a new cohort of 42 patients, finding a very high concordance between TROCAI and MCT (98%), and a good concordance (71 to 87%) with other genotypic/phenotypic methods.

Maraviroc contributes to the restoration of the homeostasis of regulatory T-cell subsets in antiretroviral-naive HIV-infected subjects.

Regulatory T (Treg) cells comprise different functional subsets with different CCR5 expression. Treg homeostasis is disrupted by HIV but the effect of treatment has barely been explored. In a longitudinal design, we compared the effect of a maraviroc-containing (n = 9) or sparing (n = 12) therapy in antiretroviral-naive HIV-positive participants on peripheral FoxP3(low) CD45RA(+) (nTreg), FoxP3(high) CD45RA(-) (eTreg) and FoxP3(low) CD45RA(-) (non-Treg) cells. Maraviroc significantly reduced all subsets in the short-term and, except for nTreg cells, also normalized them in the long-term. The correlation between eTreg cells and CD4 counts, lost before treatment, was only restored by maraviroc. The differential effect of maraviroc on Treg subsets contributes to understanding its immunomodulatory effects.

Phenotype and Polyfunctional Deregulation Involving Interleukin 6 (IL-6)- and IL-10-Producing Monocytes in HIV-Infected Patients Receiving Combination Antiretroviral Therapy Differ From Those in Healthy Older Individuals.

BACKGROUND: Despite the relevance of monocytes as promoters of the inflammatory response, whether human immunodeficiency virus (HIV) infection induces premature age-related changes to the phenotype and function of monocytes or whether these alterations are different and/or specifically driven by HIV remains to be mechanistically determined. METHODS: We assayed the activation phenotype and the responsiveness in vitro to Toll-like receptor (TLR) agonists in classical, intermediate, and nonclassical subsets of monocytes by assessing intracellular interleukin 1α (IL-1α), IL-1ß, interleukin 6 (IL-6), interleukin 8, tumor necrosis factor α, and interleukin 10 (IL-10) production in 20 HIV-infected patients receiving combination antiretroviral therapy (cART) and 2 groups of uninfected controls (20 age-matched young individuals and 20 older individuals aged >65 years). RESULTS: HIV-infected patients showed a more activated phenotype of monocytes than older controls. Regarding functionality, under unstimulated conditions HIV-infected patients showed a higher percentage of classical monocytes producing IL-6 and IL-10 than control subjects. The percentage of cells with production of multiple cytokines (polyfunctionality), including IL-10, in response to TLR agonists was greater among HIV-infected patients than among control subjects. CONCLUSIONS: Inflammatory alterations associated with monocytes during HIV infection are different from those in aging individuals. This monocyte dysfunction, mainly characterized by high levels of IL-6- and IL-10-producing monocytes, may have clinical implications in HIV-infected patients that are different from those in aging individuals.

IFNL4 ss469415590 polymorphism is associated with unfavourable clinical and immunological status in HIV-infected individuals.

The IFNL4 ss469415590 polymorphism, in high linkage disequilibrium with the IL28B rs12979860 variant, has been associated with hepatitis C virus clearance. We evaluated whether ss469415590 is associated with clinical and immunovirological parameters in human immunodeficiency virus-infected subjects. We found an independent association of the IFNL4 ss469415590 polymorphism with higher prevalence of AIDS-defining illnesses and lower CD4 T cell numbers. These results suggest the existence of common host defence mechanisms against different viral infections.

Expression of gut-homing ß7 receptor on T cells: surrogate marker for microbial translocation in suppressed HIV-1-infected patients?

OBJECTIVES: In view of the fact that mucosal damage associated with HIV-1 infection leads to microbial translocation despite successful antiretroviral treatment, we analysed microbial translocation and expression of the gut-homing ß7 receptor on peripheral T cells in HIV-1-infected individuals. METHODS: Fifteen long-term suppressed HIV-1-infected patients, of whom seven had their treatment intensified with maraviroc and eight with raltegravir, were included in the study. Samples at baseline, at week 48 of intensification, and at weeks 12 and 24 after deintensification were analysed for soluble CD14, lipopolysaccharide (LPS), LPS-binding protein, gut-homing ß7 receptor and T-cell subsets. RESULTS: The increases in both microbial translocation and expression of the gut-homing ß7 receptor on activated CD8 T cells found during maraviroc intensification were reduced after deintensification. Moreover, the correlations between activated ß7(+) T cells and LPS levels found during intensification with maraviroc (P = 0.036 and P = 0.010, respectively) were lost during deintensification. In contrast, microbial translocation was stable during raltegravir intensification, with the exception of decreased LPS levels and activated CD4 ß7(+) T cells, which reverted to baseline values after deintensification. CONCLUSIONS: Microbial translocation is an important factor in gut immune activation and mucosa inflammation, as evidenced by the association between the dynamics of microbial translocation and activated T cells expressing the gut-homing ß7 receptor. The recruitment of activated ß7(+) T cells to the gut tract when alteration of microbial translocation is maximum may be the major mechanism for recovery of mucosal integrity.

Immunological and pharmacological strategies to reactivate HIV-1 from latently infected cells: a possibility for HIV-1 paediatric patients?

The limitations to establishing a viral reservoir facilitated by early cART in children could play a critical role in achieving natural control of viral replication upon discontinuation of cART, which could be defined as 'functional cure'. Viral reservoirs could provide a persistent source of recrudescent viraemia after withdrawal of cART, despite temporary remission of HIV-1 infection, as observed in the 'Mississippi baby'. Intensification of cART has been proposed as a strategy to control residual replication and to diminish the reservoirs. The effects of cART intensification with maraviroc persisted after discontinuation of the drug in HIV-1-infected adults. However, in HIV-1-infected children, the emergence of CXCR4-using variants occurs very early, and the use of CCR5 antagonists in these children as intensification therapy may not be the best alternative. New treatments to eradicate HIV-1 are focused on the activation of viral production from latently infected cells to purge and clear HIV-1 reservoirs. This strategy involves the use of a wide range of small molecules called latency-reversing agents (LRAs). Histone deacetylase inhibitors (HDACi) such as givinostat, belinostat and panobinostat, and class I-selective HDACis that include oxamflatin, NCH-51 and romidepsin, are the most advanced in clinical testing for HIV-1 LRAs. Panobinostat and romidepsin show an efficient reactivation profile in J89GFP cells, a lymphocyte HIV-1 latently infected cell line considered a relevant model to study post-integration HIV-1 latency and reactivation. Clinical trials with panobinostat and romidepsin have been performed in children with other pathologies and it could be reasonable to design a clinical trial using these drugs in combination with cART in HIV-1-infected children.

TNF-α levels in HIV-infected patients after long-term suppressive cART persist as high as in elderly, HIV-uninfected subjects.

BACKGROUND: Chronic and systemic inflammatory alterations occur in HIV-infected patients and elderly uninfected subjects and in both scenarios these alterations are associated with the development of chronic morbidities and mortality. However, whether the levels of inflammatory alterations in untreated HIV-infected patients and elderly individuals are similar is unknown. Moreover, whether long-term antiretroviral therapy normalizes inflammatory alterations compared with HIV-uninfected persons of different age is not known. METHODS: We analysed soluble inflammatory levels [high-sensitivity C-reactive protein, interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, IL-8 and IL-17] in a cohort of viraemic HIV-infected patients compared with (i) age-matched, (ii) elderly and (iii) non-survivor elderly, uninfected healthy controls. We longitudinally analysed the effect of long-term 48 and 96 week suppressive combined antiretroviral therapy (cART) on the soluble inflammatory levels compared with those found in control subjects. RESULTS: Baseline IL-6 and IL-8 levels were at similar or lower concentrations in untreated patients compared with healthy elderly individuals. However, TNF-α and IFN-γ levels broadly exceeded those found in survivors and non-survivor elderly individuals. Long-term suppressive cART normalized most of the inflammatory markers, with the exception of TNF-α levels, which persisted as high as those in elderly non-survivor controls. CONCLUSIONS: Chronic inflammatory alterations associated with HIV infection are maintained at a different level from those of ageing. The persistent alteration of TNF-α levels in HIV-infected patients might cause tissue damage and have implications for developing non-AIDS-defining illnesses, even when HIV replication is long-term controlled by cART.

Synthesis of new anionic carbosilane dendrimers via thiol-ene chemistry and their antiviral behaviour.

A synthetic strategy has been developed for the preparation of anionic carbosilane dendrimers bearing sulfonate or carboxylate groups at their periphery by means of thiol-ene chemistry. It offers significant advantages, such as milder reaction conditions, shorter reaction times and more facile purification methods, when compared with other synthetic protocols used previously, e.g. hydrosilylation followed by a Michael-type addition or azide-alkyne coupling reactions. Molecular dynamics simulations of the second generation anionic dendrimers addressing shape and size effects of the terminal groups and conformational variability indicated that the core eccentricity and flexibility might need to be taken into account for toxicity and interaction with viral and/or cellular receptors, respectively. The biocompatibility of anionic carbosilane dendrimers has been explored showing differences between silicon-cored and polyphenoxo-cored dendrimers. In addition, silicon-cored dendrimers achieved 85-90% of HIV inhibition without inducing inflammation or vaginal irritation in mice, which makes them likely candidates for readily available, good and safe topical vaginal microbicides against HIV.

Potential of Ni(II)-NTA-modified poly(ethylene imine) glycopolymers as carrier system for future dendritic cell-based immunotherapy.

Dendritic cells (DCs) play a crucial role in the development of cell-mediated immunotherapy due to their ability to induce and maintain strong immune responses. In our study, we evaluated a biocompatible Ni(II)-NTA-modified poly(ethylene imine) dendritic glycopolymer (Ni(II)-NTA-DG) as new carrier system to increase the antigen uptake into iDCs for future DC-based immunotherapy. Ni(II)-NTA-DG led to an increase in His6-Gp160 uptake in monocytes and iDCs, where His6-Gp160 is localized in the early endosomal and lysosomal compartments. Ni(II)-NTA-DG and the formed polyplexes induced an activation of iDCs, showing an increasing expression of costimulatory molecules CD86, CD80, and proinflammatory cytokines IL-6 and IL-8. Beside no influencing effect of Ni(II)-NTA-DG and polyplexes on the maturation of antigen-bearing DCs, the mature peptide bearing DCs remained their ability to migrate along a gradient of CCR7 ligands. Thus, Ni(II)-NTA-DG with advancing biological properties is a promising carrier system for the future application in DC-based immunotherapy.

HIV infection deregulates the balance between regulatory T cells and IL-2-producing CD4 T cells by decreasing the expression of the IL-2 receptor in Treg.

Indexation of regulatory T cells (Treg) to the number of activated T cells constitutes a homeostatic mechanism ensuring that T-cell expansion remains under control. However, immune hyperactivation observed in HIV-infected patients suggests a possible dysfunction of this mechanism. Here we show that the Treg/IL-2-producing cells' balance is deeply disturbed in viremic HIV-infected patients. We found a lower expression of IL-2 receptor alpha on Treg from viremic patients. We confirmed in vitro that HIV infection of Treg downregulates IL-2 receptor alpha and phosphorylated STAT5. Our results argue for an impaired capacity of Treg to sense the expansion of activated T cells in HIV-infected patients that could contribute to the immune deregulation.

Female sex hormones regulate the Th17 immune response to sperm and Candida albicans.

STUDY QUESTION: What role do female sex hormones play in the antisperm immune response? SUMMARY ANSWER: We found that sperm induce a Th17 immune response and that estradiol down-regulates the antisperm Th17 response by dendritic cells. WHAT IS KNOWN ALREADY: Estradiol down-regulates the immune response to several pathogens and impairs the triggering of dendritic cell maturation by microbial products. STUDY DESIGN, SIZE, DURATION: Ex vivo and in vivo murine models of vaginal infection with sperm and Candida albicans were used to study the induction of Th17 and its hormonal regulation. PARTICIPANTS/MATERIALS, SETTING, METHODS: We analyzed the induction of Th17 cytokines and T cells in splenocytes obtained from BALB/c mice challenged with sperm and C. albicans. For the in vivo vaginal infection models, we used ovariectomized mice treated with vehicle, estradiol or progesterone, and we assessed the effect of these hormones on the immune response in the lymph nodes. MAIN RESULTS AND THE ROLE OF CHANCE: Th17 cytokines and T cells were induced by sperm antigens in both ex vivo and in vivo experiments. Estrus levels of estradiol down-regulated the Th17 response to sperm and C. albicans in vivo. LIMITATIONS, REASONS FOR CAUTION: This study was conducted using murine models; whether or not the results are applicable to humans is not known. WIDER IMPLICATIONS OF THE FINDINGS: Our results describe an adaptive mechanism that reconciles immunity and reproduction and further explains why unregulated Th17 could be linked to infertility and recurrent infections. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by research grants from the Instituto de Salud Carlos III (ISCIII) (PI10/00897) and Fundación Mutua Madrileña to M.R. M.R. holds a Miguel Servet contract from the ISCIII (CP08/00228). M.A.M.-F. was supported by (ISCIII) INTRASALUD PI09/02029. We have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: Not required.