Kidney transplant recipients (KTRs) face a significantly elevated risk of persistent high-risk human papillomavirus (HR-HPV) infection and subsequent anal squamous cell carcinoma (ASCC) due to chronic immunosuppressive therapy impairing immunosurveillance. Despite the markedly increased risk of ASCC in this vulnerable cohort, standardized screening protocols and optimal clinical management guidelines are not exhaustive. Chronically compromised immunosurveillance permits prolonged HR-HPV carriage and viral genome integration, driving oncogenesis via the E6 and E7 oncoproteins. While calcineurin inhibitors exert pro-oncogenic effects, transitioning to mTOR inhibitors offers distinct antiproliferative and antiviral advantages. Early detection relies on risk-stratified screening utilizing digital anorectal examination, anal cytology, and high-resolution anoscopy. For managing anal intraepithelial neoplasia, traditional topical agents and minimally invasive ablative procedures are widely used, although high recurrence rates present a major clinical challenge. This review analyzes HPV pathogenesis and clinical management in KTRs, evaluating the impact of immunosuppressive regimens and exploring innovative diagnostic and therapeutic strategies. To address viral persistence without compromising the allograft, integrating novel non-invasive, target-specific nutraceuticals may represent an interesting complementary approach. Ultimately, mitigating post-transplant ASCC requires a multidisciplinary strategy that couples early localized screening with tailored systemic immunosuppression.

HIV vaccines and antibody-based prevention strategies targeting Env have shown limited efficacy. Here, we identify a Tat-dependent mechanism of HIV transmission and immune evasion mediated by extracellular Tat (eTat), a viral protein expressed early after infection and abundantly released into tissues. Extracellular Tat binds heparan sulfate proteoglycans and, when immobilized, mimics extracellular matrix proteins. We show here that immobilized eTat efficiently captures HIV virions from multiple clades and tiers. Although only a small fraction of virions is retained, Tat-bound virus displays enhanced infectivity, particularly at low virus inputs, a process we term Tat-assisted infection. Notably, both first- and second-generation anti-Env broadly neutralizing antibodies (bnAbs) fail to prevent virion capture and show strongly reduced neutralization potency against Tat-captured viruses, irrespective of epitope specificity. In contrast, polyclonal and monoclonal anti-Tat antibodies efficiently block both virus capture and infection. These findings reveal that eTat establishes an extracellular pool of highly infectious, neutralization-resistant virions, providing a mechanistic explanation for the limited efficacy of current Env-focused interventions. Our work identifies Tat as a critical and targetable determinant of HIV infectivity and immune evasion, supporting the inclusion of Tat in next-generation preventive and therapeutic vaccine strategies and in passive immunization approaches combined with bnAbs.

We are pleased to present this closing editorial for the Special Issue “Vaccines and Vaccination: HIV, Hepatitis Viruses and HPV”, which we had the privilege of coordinating [...]

Introduction:Antiretroviral therapy (ART) suppresses HIV replication but fails to eradicate viral reservoirs or fully restore immune competence. Therapeutic vaccination targeting HIV-1 Tat, a key viral protein persistently expressed also during ART, may enhance immune reconstitution and limit reservoir maintenance. Long-term data in individuals infected with HIV-1 clade C, particularly in sub-Saharan Africa, are lacking. Methods:We conducted a 12-year extended follow-up of 161 ART-treated adults previously enrolled in a randomized, placebo-controlled phase 2 trial of therapeutic HIV-1 Tat vaccination in South Africa (ISS T-003; SANCTR n. DOH-27-0211-3351; ClinicalTrials.gov: NCT01513135). No booster immunizations were administered. Longitudinal outcomes included anti-Tat antibody (Ab) persistence, CD4+ T-cell counts, plasma HIV RNA, and total HIV DNA in peripheral CD4+ T cells. Analyses were stratified by sex and ART adherence. Results:Ninety-seven percent of vaccinees developed anti-Tat Abs after immunization, and 70% were still positive at the beginning of the extended follow-up (3 years). Among these, 39% maintained Ab responses for their entire observation period (median duration 4 years), and 17 participants (20%) remained anti-Tat Ab seropositive up to year 12. Moreover, both Ab durability and peak titers were greater in vaccinees than in naturally occurring antibodies in seroconverter placebos. Compared with placebo, Tat vaccination was associated with earlier and sustained CD4+ T-cell recovery and accelerated decline of total HIV DNA, effects that persisted for more than a decade. These benefits were most pronounced in men, who were more immunocompromised at baseline, and in individuals with suboptimal ART adherence. Notably, vaccinated participants with intermittent viremia maintained stable or increasing CD4+ T-cell counts and continued reservoir reduction over time. Discussion:Therapeutic HIV-1 Tat vaccination induces long-lasting immunological benefits that extend beyond viral suppression achieved by ART alone, promoting durable immune reconstitution and progressive reservoir decay in clade C infection. These findings confirm results from a long-term follow-up of a parallel phase 2 trial in Italy, and both support Tat vaccination as a potential ART-intensifying strategy, particularly in populations with advanced immunosuppression or imperfect ART adherence. Trial registration:SANCTR n. DOH-27-0615-4948 and ClinicalTrials.gov: NCT02712489; and SANCTR n. DOH-27-072022-7347 and ClinicalTrials.gov: NCT05680948.

Supplementary Table 2 shows the treatment-related AE numbers by study phases.

Lenvatinib is a multityrosine kinase inhibitor approved for progressive radioiodine refractory differentiated thyroid cancer (RAI-R-DTC). Despite its efficacy, most of the initial experiences showed global inferior results if compared with SELECT study. Baseline disease stages, previous systemic treatments and baseline patients’ characteristics may affect response to therapy. The aim of our study was to review relevant clinical outcomes, identifying survival predictors, of a single center cohort of patients with advanced thyroid cancer treated with Lenvatinib. Twenty-two patients with progressive RAIR-R-DTC treated with Lenvatinib were retrospectively included. For each patient, we reviewed the main clinical baseline characteristics, including nutritional status. We evaluated the latter by using CONtrolling NUTritional status (CONUT) score. Clinical outcomes were overall survival (OS) and progression free survival (PFS). At the time of analysis, 14 patients (63.6

Supplementary Table 4 shows the treatment-related laboratory AE by SOC, preferred terms and study phases.

Supplementary Table 3 shows the clinical treatment-related AEs by SOC and study phases.

Supplementary Table 1 shows the active concurrent illnesses at baseline.

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/β-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 β-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, β-catenin is overexpressed, suggesting that Wnt/β-catenin pathway activation drives immune exclusion through CCL4 downregulation.Further analysis indicated that loss of p53 function is inversely correlated with β-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/β-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.

Supplementary Table 5 summarizes the representativeness of study participants

Human papillomavirus (HPV) infection represents one of the most common sexually transmitted infections worldwide. However, the lack of effective therapeutic strategies to counteract viral infection and its persistence still makes the management of HPV a medical concern. Persistence is indeed a crucial issue in the context of HPV, as it may increase the risk of viral DNA integration into the host genome, thus exposing patients to tumoral progression. This clinical study aims to evaluate the effectiveness of a dietary supplement containing epigallocatechin gallate (EGCG), folic acid (FA), vitamin B12 (B12), and hyaluronic acid (HA) in improving HPV clearance and HPV-induced cervical lesions, and in counteracting viral persistence. A total of 106 patients who tested positive for HPV DNA were enrolled in this study and were treated daily for 6 months with a tablet containing EGCG (200 mg), FA (400 μg), B12 (1 mg), and HA (50 mg) (Pervistop®, Lo.Li. Pharma, Rome, Italy). A 6-month treatment with such combined molecules demonstrated a viral clearance in 85.8% of enrolled patients, while 92.3% of participants exhibited no more cervical lesions. Furthermore, 71.8% of patients with persistent infection tested negative to HPV DNA test after 6 months of treatment. The obtained data in this large population strongly support previous evidence on the efficacy of such molecules in the management of HPV infection by improving both viral clearance and related cervical lesions, and by targeting viral persistence.

Baseline characteristics of study participants

Immunological parameters in participants that entered the maintenance phase (n = 16). Levels at enrolment, upon induction and during maintenance and post-therapy follow-up of total lymphocytes absolute number (103 cells/μL; A), CD4+ (B) CD8+, and (C) T-cell number (cells/μL), CD4+/CD8+ ratio (D), B- (E), and NK- (F) cell number (cells/μL). Data are presented as box plots. Wilcoxon signed rank sum test for paired data and Mann–Whitney test were used for the analyses. P values assess the changes from enrolment and from baseline of maintenance within responders and progressors and differences between responders and progressors at each time point.

Clinical responses upon induction (6–8 months), maintenance (12 months), and post-therapy follow-up (12 months)

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.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.

Active MMP-2, CEC, and EPC levels and NK activity in participants that entered the maintenance phase (n = 16). Shown are the levels (cells/mL) at enrolment, upon induction, during maintenance, and post-therapy follow-up of active MMP-2 (A), CEC (B), and EPC (C), and NK-cell activity against K562 (D) or BCBL-1 targets (E) as % of lysis. Data are presented as box plots. Wilcoxon signed rank sum test for paired data and Mann–Whitney test were used for the analyses. P values assess the changes from enrolment and from baseline of maintenance within responders and progressors and differences between responders and progressors at each time point.

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.