Wnt/B-catenin activation and TP53 mutations associate with distinct immune profiles in advanced thyroid cancer.

CONTEXT: Anaplastic thyroid carcinomas (ATCs) and poorly differentiated thyroid carcinomas (PDTCs) exhibit distinct immune-related gene expression profiles. Most ATCs are characterized by active immune interactions (hot or altered immunosuppressed immunophenotypes), while PDTCs are largely immunologically inert (cold immunophenotypes). OBJECTIVE: This study aimed to elucidate the mechanisms driving these divergent immunological fates, focusing on the Wnt/ß-catenin pathway and TP53 mutations. RESULTS: Our data reveal that ATCs frequently harbor TP53 mutations (83.3%), which correlate with a hot immunophenotype, characterized by high expression of ß-catenin-regulated cytokine CCL4 and recruitment of CD103+ dendritic cells. Conversely, PDTCs, with a lower incidence of TP53 mutations (12.5%), often exhibit a cold immunophenotype. In cold cancers and PDTCs, ß-catenin is overexpressed suggesting that Wnt/ß-catenin pathway activation drives immune exclusion through CCL4 downregulation.Further analysis indicated that loss of p53 function is inversely correlated with ß-catenin expression. P53-mutated cancers showed significantly higher expression of CCL4 and densities of CD103+ dendritic cells compared to their p53-wild-type counterparts. Additionally, p53-mutated ATCs expressed a higher number of immune-related genes, supporting the role of p53 loss in activating immune responses in cancer. CONCLUSION: Our study indicates a potential correlation between the activation of the Wnt/ß-catenin pathway and the development of cold thyroid cancers, which may be mediated by the suppression of CCL4 expression. Concurrently, mutations in the p53 gene appear to be linked with the occurrence of hot thyroid cancers. While these associations are compelling, they are based on observational data. Experimental research is necessary to determine the causal relationships underlying these findings.

Clinical Efficacy of the HIV Protease Inhibitor Indinavir in Combination with Chemotherapy for Advanced Classic Kaposi Sarcoma Treatment: A Single-Arm, Phase II Trial in the Elderly.

Kaposi sarcoma is a rare angioproliferative disease associated with human herpes virus-8 (HHV-8) infection. Kaposi sarcoma is frequent and aggressive in HIV-infected people, whereas the classic form (CKS) generally has an indolent course. Notably, all conventional therapies against Kaposi sarcoma have only temporary efficacy. We have previously shown that indinavir, a HIV protease-inhibitor with direct antiangiogenic and antitumor activity, is safe and effective in patients with early CKS, whereas effects are less prominent in advanced disease, probably due to the larger tumor mass. Therefore, the clinical response to indinavir was assessed in patients with advanced CKS after debulking chemotherapy. This was a monocentric phase 2 trial in elderly with progressive/advanced CKS treated with debulking chemotherapy and indinavir combined, followed by a maintenance phase with indinavir alone. Secondary endpoints included safety and Kaposi sarcoma biomarker evaluation.All evaluable patients (22) responded to debulking therapy. Out of these, 16 entered the indinavir maintenance phase. The overall response rate at end of maintenance was 75% (estimated median response-duration 43 months). Moreover, most responders showed further clinical improvements (lesion number/nodularity) during maintenance and post-treatment follow-up. Notably, after relapse, progressors did not require systemic Kaposi sarcoma therapy and showed clinical improvements (including disease stabilization) remaining on study. Responders also showed immune status amelioration with a consistent B-cell increase and positive changes of other biomarkers, including anti-HHV-8 natural killer activity. In advanced CKS a strategy combining indinavir and chemotherapy is safe and associated with high and durable response rates and it could be rapidly adopted for the clinical management of these patients. SIGNIFICANCE: This phase-2 trial showed that the HIV protease inhibitor indinavir may boost and extend the duration of the effects of chemotherapy in elderly with advanced progressive classic Kaposi sarcoma, without additional toxicity. Further, the amelioration of the immune status seen in responders suggests a better control of HHV-8 infection and tumor-cell killing. Thus, indinavir combined with chemotherapy may represent an important tool for the clinical management of classic Kaposi sarcoma in elderly patients.

Monitoring Monkeypox: Safeguarding Global Health through Rapid Response and Global Surveillance.

Monkeypox, a viral zoonotic disease, has emerged as a significant global threat in recent years. This review focuses on the importance of global monitoring and rapid response to monkeypox outbreaks. The unpredictable nature of monkeypox transmissions, its potential for human-to-human spread, and its high morbidity rate underscore the necessity for proactive surveillance systems. By analyzing the existing literature, including recent outbreaks, this review highlights the critical role of global surveillance in detecting, containing, and preventing the further spread of monkeypox. It also emphasizes the need for enhanced international collaboration, data sharing, and real-time information exchange to effectively respond to monkeypox outbreaks as a global health concern. Furthermore, this review discusses the challenges and opportunities of implementing robust surveillance strategies, including the use of advanced diagnostic tools and technologies. Ultimately, these findings underscore the urgency of establishing a comprehensive global monitoring framework for monkeypox, enabling early detection, prompt response, and effective control measures to protect public health worldwide.

HIV-1-Host Interaction in Gut-Associated Lymphoid Tissue (GALT): Effects on Local Environment and Comorbidities.

HIV-1 replication in the gastrointestinal (GI) tract causes severe CD4+ T-cell depletion and disruption of the protective epithelial barrier in the intestinal mucosa, causing microbial translocation, the main driver of inflammation and immune activation, even in people living with HIV (PLWH) taking antiretroviral drug therapy. The higher levels of HIV DNA in the gut compared to the blood highlight the importance of the gut as a viral reservoir. CD4+ T-cell subsets in the gut differ in phenotypic characteristics and differentiation status from the ones in other tissues or in peripheral blood, and little is still known about the mechanisms by which the persistence of HIV is maintained at this anatomical site. This review aims to describe the interaction with key subsets of CD4+ T cells in the intestinal mucosa targeted by HIV-1 and the role of gut microbiome and its metabolites in HIV-associated systemic inflammation and immune activation that are crucial in the pathogenesis of HIV infection and related comorbidities.

Eosinophils as potential biomarkers in respiratory viral infections.

Eosinophils are bone marrow-derived granulocytes that, under homeostatic conditions, account for as much as 1-3% of peripheral blood leukocytes. During inflammation, eosinophils can rapidly expand and infiltrate inflamed tissues, guided by cytokines and alarmins (such as IL-33), adhesion molecules and chemokines. Eosinophils play a prominent role in allergic asthma and parasitic infections. Nonetheless, they participate in the immune response against respiratory viruses such as respiratory syncytial virus and influenza. Notably, respiratory viruses are associated with asthma exacerbation. Eosinophils release several molecules endowed with antiviral activity, including cationic proteins, RNases and reactive oxygen and nitrogen species. On the other hand, eosinophils release several cytokines involved in homeostasis maintenance and Th2-related inflammation. In the context of SARS-CoV-2 infection, emerging evidence indicates that eosinophils can represent possible blood-based biomarkers for diagnosis, prognosis, and severity prediction of disease. In particular, eosinopenia seems to be an indicator of severity among patients with COVID-19, whereas an increased eosinophil count is associated with a better prognosis, including a lower incidence of complications and mortality. In the present review, we provide an overview of the role and plasticity of eosinophils focusing on various respiratory viral infections and in the context of viral and allergic disease comorbidities. We will discuss the potential utility of eosinophils as prognostic/predictive immune biomarkers in emerging respiratory viral diseases, particularly COVID-19. Finally, we will revisit some of the relevant methods and tools that have contributed to the advances in the dissection of various eosinophil subsets in different pathological settings for future biomarker definition.

Cellular Immune Profiling of Lung and Blood Compartments in Patients with SARS-CoV-2 Infection.

BACKGROUND: SARS-CoV-2 related immunopathology may be the driving cause underlying severe COVID-19. Through an immunophenotyping analysis on paired bronchoalveolar lavage fluid (BALF) and blood samples collected from mechanically ventilated patients with COVID-19-associated Acute Respiratory Distress Syndrome (CARDS), this study aimed to evaluate the cellular immune responses in survivors and non-survivors of COVID-19. METHODS: A total of 36 paired clinical samples of bronchoalveolar lavage fluid (BALF) mononuclear cells (BALF-MC) and peripheral blood mononuclear cells (PBMC) were collected from 18 SARS-CoV-2-infected subjects admitted to the intensive care unit (ICU) of the Policlinico Umberto I, Sapienza University Hospital in Rome (Italy) for severe interstitial pneumonia. The frequencies of monocytes (total, classical, intermediate and non-classical) and Natural Killer (NK) cell subsets (total, CD56bright and CD56dim), as well as CD4+ and CD8+ T cell subsets [naïve, central memory (TCM) and effector memory (TEM)], and those expressing CD38 and/or HLADR were evaluated by multiparametric flow cytometry. RESULTS: Survivors with CARDS exhibited higher frequencies of classical monocytes in blood compared to non-survivors (p < 0.05), while no differences in the frequencies of the other monocytes, NK cell and T cell subsets were recorded between these two groups of patients (p > 0.05). The only exception was for peripheral naïve CD4+ T cells levels that were reduced in non-survivors (p = 0.04). An increase in the levels of CD56bright (p = 0.012) and a decrease in CD56dim (p = 0.002) NK cell frequencies was also observed in BALF-MC samples compared to PBMC in deceased COVID-19 patients. Total CD4+ and CD8+ T cell levels in the lung compartment were lower compared to blood (p = 0.002 and p < 0.01, respectively) among non-survivors. Moreover, CD38 and HLA-DR were differentially expressed by CD4+ and CD8+ T cell subsets in BALF-MC and in PBMC among SARS-CoV-2-infected patients who died from COVID-19 (p < 0.05). CONCLUSIONS: These results show that the immune cellular profile in blood and pulmonary compartments was similar in survivors and non-survivors of COVID-19. T lymphocyte levels were reduced, but resulted highly immune-activated in the lung compartment of patients who faced a fatal outcome.

Turning a Tumor Microenvironment Pitfall into Opportunity: Discovery of Benzamidoxime as PD-L1 Ligand with pH-Dependent Potency.

PD-1/PD-L1 protein complex is attracting a great deal of interest as a drug target for the design of immune therapies able to block its assembly. Although some biologic drugs have entered clinical use, their poor response rate in patients are demanding further efforts to design small molecule inhibitors of PD-1/PD-L1 complex with higher efficacy and optimal physicochemical properties. Dysregulation of pH in the tumor microenvironment is indeed one of the key mechanisms promoting drug resistance and lack of response in cancer therapy. Integrating computational and biophysical approaches, herein we report a screening campaign that has led to identifying VIS310 as a novel ligand of PD-L1, with physicochemical properties enabling a pH-dependent binding potency. Additional optimization efforts by analogue-based screening have been instrumental to disclosing VIS1201, which exhibits improved binding potency against PD-L1 and is able to inhibit PD-1/PD-L1 complex formation in a ligand binding displacement assay. While providing preliminary structure-activity relationships (SARs) of a novel class of PD-L1 ligands, our results lay the foundation for the discovery of immunoregulatory small molecules resilient to tumor microenvironmental conditions for escaping drug-resistance mechanisms.

Clinical Impact of Colonization with Carbapenem-Resistant Gram-Negative Bacteria in Critically Ill Patients Admitted for Severe Trauma.

Multidrug-resistant (MDR) Gram-negative bacteria (GNB) have raised concerns as common, frequent etiologic agents of nosocomial infections, and patients admitted to intensive care units (ICUs) present the highest risk for colonization and infection. The incidence of colonization and infection in trauma patients remains poorly investigated. The aim of this study was to assess the risk factors for Carbapenem-resistant (CR)-GNB colonization and the clinical impact of colonization acquisition in patients with severe trauma admitted to the ICU in a CR-GNB hyperendemic country. This is a retrospective observational study; clinical and laboratory data were extracted from the nosocomial infection surveillance system database. Among 54 severe trauma patients enrolled in the study, 28 patients were colonized by CR-GNB; 7 (12.96%) patients were already colonized at ICU admission; and 21 (38.89%) patients developed a new colonization during their ICU stay. Risk factors for colonization were the length of stay in the ICU (not colonized, 14.81 days ± 9.1 vs. colonized, 38.19 days ± 27.9; p-value = 0.001) and days of mechanical ventilation (not colonized, 8.46 days ± 7.67 vs. colonized, 22.19 days ± 15.09; p-value < 0.001). There was a strong statistical association between previous colonization and subsequent development of infection (OR = 80.6, 95% CI 4.5−1458.6, p-value < 0.001). Factors associated with the risk of infection in colonized patients also included a higher Charlson comorbidity index, a longer length of stay in the ICU, a longer duration of mechanical ventilation, and a longer duration of treatment with carbapenem and vasopressors (not infected vs. infected: 0(0−4) vs. 1(0−3), p = 0.012; 24.82 ± 16.77 vs. 47 ± 28.51, p = 0.016; 13.54 ± 15.84 vs. 31.7 ± 16.22, p = 0.008; 1.09 ± 1.14 vs. 7.82 ± 9.15, p = 0.008). The adoption of MDR-GNB colonization prevention strategies in critically ill patients with severe trauma is required to improve the quality of care and reduce nosocomial infections, length of hospital stay and mortality.

Short- and Long-Term Immunological Responses in Chronic HCV/HIV Co-Infected Compared to HCV Mono-Infected Patients after DAA Therapy.

BACKGROUND: Direct-acting antivirals (DAAs) treatment, although highly efficacious for the treatment of hepatitis C virus (HCV) infection, may not completely reconstitute the HCV-mediated dysregulated immune system, especially in patients co-infected with human immunodeficiency virus (HIV) and HCV. OBJECTIVES: We aimed to evaluate the impact of HCV eradication following DAA therapy on the immune system and liver disease improvement through comparative monitoring of 10 HCV mono-infected and 10 HCV/HIV co-infected patients under combined antiretroviral therapy (cART). Early and late longitudinal phenotypic changes in peripheral blood mononuclear cell (PBMC) subsets, T-cell activation, differentiation and exhaustion, as well as inflammatory biomarkers, indoleamine 2-3 dioxygenase (IDO) activity, and liver stiffness, APRI and FIB-4 scores were assessed. MATERIALS AND METHODS: Samples were obtained at baseline (T0), week 1 (T1), week 2 (T2), week 12 (T3, end of treatment, EOT), and month 9 (T4, end of follow-up, 36 weeks post EOT). RESULTS: All patients achieved a sustained virological response (SVR 12) after DAA treatment. Overall, changes of the T-cell immune phenotypes were greater in HCV/HIV co-infected than in HCV mono-infected, due to an increase in CD4+ and CD8+ T-cell percentages and of CD8+ T-cell activation and memory markers, in particular at the end of follow-up. On the other end, HCV mono-infected showed changes in the activation profile and in the memory CD4+ T-cell compartment. In HCV/HIV co-infected, a decrease in the IDO activity by DAA treatment was observed; conversely, in HCV mono-infected, it resulted unmodified. Regarding inflammatory mediators, viral suppression was associated with a reduction in IP-10 levels, while interferon regulatory factor (IRF)-7, interferon (IFN)-ß, and interferon (IFN)-γ levels were downregulated during therapy and increased post therapy. A decrease in liver stiffness, APRI, and FIB-4 scores was also observed. CONCLUSIONS: Our study suggests that, although patients achieved HCV eradication, the immune activation state in both HCV mono-infected and HCV/HIV co-infected patients remains elevated for a long time after the end of DAA therapy, despite an improvement of liver-specific outcomes, meanwhile highlighting the distinct immunophenotypic and inflammatory biomarker profile between the groups of patients.

Impact of Epithelial-Mesenchymal Immunophenotype on Local Aggressiveness in Papillary Thyroid Carcinoma Invading the Airway.

Primary thyroid tumours show different levels of aggressiveness, from indolent to rapidly growing infiltrating malignancies. The most effective therapeutic option is surgery when radical resection is feasible. Biomarkers of aggressiveness may help in scheduling extended resections such as airway infiltration, avoiding a non-radical approach. The aim of the study is to evaluate the prognostic role of E-cadherin, N-cadherin, Aryl hydrocarbon receptor (AhR), and CD147 in different biological behaviours. Fifty-five samples from three groups of thyroid carcinomas were stained: papillary thyroid carcinomas (PTCs) infiltrating the airway (PTC-A), papillary intra-thyroid carcinomas (PTC-B) and poorly differentiated or anaplastic thyroid carcinomas (PDTC/ATC). High expressions of N-cadherin and AhR were associated with higher locoregional tumour aggressiveness (p = 0.005 and p < 0.001 respectively); PDTC/ATC more frequently showed a high expression of CD147 (p = 0.011), and a trend of lower expression of E-cadherin was registered in more aggressive neoplasms. Moreover, high levels of AhR were found with recurrent/persistent diseases (p = 0.031), particularly when tumours showed a concomitant high N-cadherin expression (p = 0.043). The study suggests that knowing in advance onco-biological factors with a potential role to discriminate between different subsets of patients could help the decision-making process, providing a more solid therapeutic indication and an increased expectation for radical surgery.

New insights into pathogenesis point to HIV-1 Tat as a key vaccine target.

Despite over 30 years of enormous effort and progress in the field, no preventative and/or therapeutic vaccines against human immunodeficiency virus (HIV) are available. Here, we briefly summarize the vaccine strategies and vaccine candidates that in recent years advanced to efficacy trials with mostly unsatisfactory results. Next, we discuss a novel and somewhat contrarian approach based on biological and epidemiological evidence, which led us to choose the HIV protein Tat for the development of preventive and therapeutic HIV vaccines. Toward this goal, we review here the role of Tat in the virus life cycle as well as experimental and epidemiological evidence supporting its key role in the natural history of HIV infection and comorbidities. We then discuss the preclinical and clinical development of a Tat therapeutic vaccine, which, by improving the functionality and homeostasis of the immune system and by reducing the viral reservoir in virologically suppressed vaccinees, helps to establish key determinants for intensification of combination antiretroviral therapy (cART) and a functional cure. Future developments and potential applications of the Tat therapeutic vaccine are also discussed, as well as the rationale for its use in preventative strategies. We hope this contribution will lead to a reconsideration of the current paradigms for the development of HIV/AIDS vaccines, with a focus on targeting of viral proteins with key roles in HIV pathogenesis.

Advances in SIV/SHIV Non-Human Primate Models of NeuroAIDS.

Non-human primates (NHPs) are the most relevant model of Acquired Immunodeficiency Syndrome (AIDS) and neuroAIDS, being of great importance in explaining the pathogenesis of HIV-induced nervous system damage. Simian Immunodeficiency Virus (SIV)/ Simian-Human Immunodeficiency Virus (SHIV)-infected monkeys have provided evidence of complex interactions between the virus and host that include host immune response, viral genetic diversity, and genetic susceptibility, which may explain virus-associated central nervous system (CNS) pathology and HIV-associated neurocognitive disorders (HAND). In this article, we review the recent progress contributions obtained using monkey models of HIV infection of the CNS, neuropathogenesis and SIV encephalitis (SIVE), with an emphasis on pharmacologic therapies and dependable markers that predict development of CNS AIDS.

Anti-Tat immunity defines CD4+ T-cell dynamics in people living with HIV on long-term cART.

BACKGROUND: Low-level HIV viremia originating from virus reactivation in HIV reservoirs is often present in cART treated individuals and represents a persisting source of immune stimulation associated with sub-optimal recovery of CD4+ T cells. The HIV-1 Tat protein is released in the extracellular milieu and activates immune cells and latent HIV, leading to virus production and release. However, the relation of anti-Tat immunity with residual viremia, persistent immune activation and CD4+ T-cell dynamics has not yet been defined. METHODS: Volunteers enrolled in a 3-year longitudinal observational study were stratified by residual viremia, Tat serostatus and frequency of anti-Tat cellular immune responses. The impact of anti-Tat immunity on low-level viremia, persistent immune activation and CD4+ T-cell recovery was investigated by test for partitions, longitudinal regression analysis for repeated measures and generalized estimating equations. FINDINGS: Anti-Tat immunity is significantly associated with higher nadir CD4+ T-cell numbers, control of low-level viremia and long-lasting CD4+ T-cell recovery, but not with decreased immune activation. In adjusted analysis, the extent of CD4+ T-cell restoration reflects the interplay among Tat immunity, residual viremia and immunological determinants including CD8+ T cells and B cells. Anti-Env immunity was not related to CD4+ T-cell recovery. INTERPRETATION: Therapeutic approaches aiming at reinforcing anti-Tat immunity should be investigated to improve immune reconstitution in people living with HIV on long-term cART. TRIAL REGISTRATION: ISS OBS T-002 ClinicalTrials.gov identifier: NCT01024556 FUNDING: Italian Ministry of Health, special project on the Development of a vaccine against HIV based on the Tat protein and Ricerca Corrente 2019/2020.

PD-1 blockade delays tumor growth by inhibiting an intrinsic SHP2/Ras/MAPK signalling in thyroid cancer cells.

BACKGROUND: The programmed cell death-1 (PD-1) receptor and its ligands PD-L1 and PD-L2 are immune checkpoints that suppress anti-cancer immunity. Typically, cancer cells express the PD-Ls that bind PD-1 on immune cells, inhibiting their activity. Recently, PD-1 expression has also been found in cancer cells. Here, we analysed expression and functions of PD-1 in thyroid cancer (TC). METHODS: PD-1 expression was evaluated by immunohistochemistry on human TC samples and by RT-PCR, western blot and FACS on TC cell lines. Proliferation and migration of TC cells in culture were assessed by BrdU incorporation and Boyden chamber assays. Biochemical studies were performed by western blot, immunoprecipitation, pull-down and phosphatase assays. TC cell tumorigenicity was assessed by xenotransplants in nude mice. RESULTS: Human TC specimens (47%), but not normal thyroids, displayed PD-1 expression in epithelial cells, which significantly correlated with tumour stage and lymph-node metastasis. PD-1 was also constitutively expressed on TC cell lines. PD-1 overexpression/stimulation promoted TC cell proliferation and migration. Accordingly, PD-1 genetic/pharmacologic inhibition caused the opposite effects. Mechanistically, PD-1 recruited the SHP2 phosphatase to the plasma membrane and potentiated its phosphatase activity. SHP2 enhanced Ras activation by dephosphorylating its inhibitory tyrosine 32, thus triggering the MAPK cascade. SHP2, BRAF and MEK were necessary for PD-1-mediated biologic functions. PD-1 inhibition decreased, while PD-1 enforced expression facilitated, TC cell xenograft growth in mice by affecting tumour cell proliferation. CONCLUSIONS: PD-1 circuit blockade in TC, besides restoring anti-cancer immunity, could also directly impair TC cell growth by inhibiting the SHP2/Ras/MAPK signalling pathway.

The Stone Guest: How Does pH Affect Binding Properties of PD-1/PD-L1 Inhibitors?

The interaction between programmed cell death-1 (PD-1) and its ligand PD-L1 activates a coinhibitory signal that blocks T-cell activation, promoting the immune escape process in the tumor microenvironment. Development of monoclonal antibodies targeting and inhibiting PD-1/PD-L1 interaction as anticancer immunotherapies has proved successful in multiple clinical settings and for various types of cancer. Notwithstanding, limitations exist with the use of these biologics, including drug resistance and narrow therapeutic response rate in a majority of patients, that demand for the design of more efficacious small molecule-based immunotherapies. Alteration of pH in the tumor microenvironment is a key factor that is involved in promoting drug resistance, tumor survival and progression. In this study, we have investigated the effect of pH shifts on binding properties of distinct classes of PD-L1 inhibitors, including macrocyclic peptide and small molecules. Results expand structure-activity relationships of PD-L1 inhibitors, providing insights into structural features and physicochemical properties that are useful for the design of ligands that may escape a drug resistance mechanism associated to variable pH conditions of tumor microenvironment.

THERAPY OF ENDOCRINE DISEASE Immunotherapy of advanced thyroid cancer: from bench to bedside.

Immunotherapy has arisen in use in the field of oncology with seven immune checkpoint inhibitors approved for the treatment of a variety of cancer histologies. Depending on the cancer type, the success rate might be different, but in average it is about 20%, with some cases showing a durable response, lasting also after the interruption of the treatment, with a clear benefit on OS. The development of an efficacious cure for advanced thyroid carcinomas is still an unmet need and immunotherapy represents an interesting alternative option also for this cancer. However, very few clinical trials have been accomplished and very few studies exploring a way to overcome resistance have been performed. In this review, we will summarize the mechanisms of immune escape, with a special reference to follicular-derived thyroid carcinoma. Furthermore, we will try to speculate on the use of immune checkpoint inhibitors for the treatment of follicular-derived advanced thyroid carcinoma. Finally, we will summarize the ongoing clinical trials and the future directions of the field.

HIV therapeutic vaccines aimed at intensifying combination antiretroviral therapy.

Introduction: Although successful at suppressing HIV replication, combination antiretroviral therapy (cART) only partially restores immune functions and fails to reduce the latent HIV reservoir, thus requiring novel interventions for its intensification.Areas covered: Here are reviewed therapeutic vaccine candidates that are being developed to this goal. Among them, the Tat vaccine has been shown to promote immune restoration, including CD4+ T-cell recovery in low immunological responders, and to reduce the virus reservoirs well beyond what achieved with long-term suppressive cART.Expert opinion: The authors propose the Tat vaccine as a promising vaccine candidate for cART intensification toward HIV reservoirs depletion, functional cure, and eradication strategies, suggesting that targeting a key protein in the virus life cycle is pivotal to success.

The Aryl Hydrocarbon Receptor Is Expressed in Thyroid Carcinoma and Appears to Mediate Epithelial-Mesenchymal-Transition.

Aryl hydrocarbon receptor (AhR) is expected to promote initiation, progression and invasion of cancer cells regulating proliferation, differentiation, gene expression, inflammation, cell motility and migration. Furthermore, an immunosuppressant function of AhR has been recognized. This study evaluated AhR expression and its role in thyroid cancer progression. AhR expression was assessed by qPCR in 107 thyroid cancer samples (90 PTCs, 11 MTCs, 6 ATCs), and by immunohistochemistry in 41 PTCs. To estimate receptor activation, the expression of target genes CYP1A1 and CYP1B1 was measured. AhR functional effects were evaluated in kynurenine-stimulated FTC-133 and BcPap cell lines by analyzing the expression of genes involved in EMT and cell motility. AhR mRNA expression resulted significantly higher in all the analyzed thyroid cancer samples compared to normal thyroid and a statistically significant correlation with CYP1B1 was detected. Kynurenine-stimulated FTC-133 and BcPap showed the activation of a specific AhR-driven EMT program characterized by E-cadherin decrease and SLUG, N-cadherin and fibronectin increase, resulting in boost of cell motility and invasion. This study confirmed the importance of the IDO1-Kyn-AhR pathway in thyroid cancer tumorigenesis, suggesting an AhR pivotal role in mediating an immunosuppressive microenvironment and favoring the acquisition of a mesenchymal phenotype that could promote invasiveness and metastasis.

HIV-1 Tat Protein Enters Dysfunctional Endothelial Cells via Integrins and Renders Them Permissive to Virus Replication.

Previous work has shown that the Tat protein of Human Immunodeficiency Virus (HIV)-1 is released by acutely infected cells in a biologically active form and enters dendritic cells upon the binding of its arginine-glycine-aspartic acid (RGD) domain to the α5ß1, αvß3, and αvß5 integrins. The up-regulation/activation of these integrins occurs in endothelial cells exposed to inflammatory cytokines that are increased in HIV-infected individuals, leading to endothelial cell dysfunction. Here, we show that inflammatory cytokine-activated endothelial cells selectively bind and rapidly take up nano-micromolar concentrations of Tat, as determined by flow cytometry. Protein oxidation and low temperatures reduce Tat entry, suggesting a conformation- and energy-dependent process. Consistently, Tat entry is competed out by RGD-Tat peptides or integrin natural ligands, and it is blocked by anti-α5ß1, -αvß3, and -αvß5 antibodies. Moreover, modelling-docking calculations identify a low-energy Tat-αvß3 integrin complex in which Tat makes contacts with both the αv and ß3 chains. It is noteworthy that internalized Tat induces HIV replication in inflammatory cytokine-treated, but not untreated, endothelial cells. Thus, endothelial cell dysfunction driven by inflammatory cytokines renders the vascular system a target of Tat, which makes endothelial cells permissive to HIV replication, adding a further layer of complexity to functionally cure and/or eradicate HIV infection.