Natural infection with dengue virus (DENV) induces an increase in the production of cytokines that play an important role in disease pathogenesis. Despite numerous scientific studies, there are still no commercially available disease-specific therapeutics. Previous evidence shows that inhibiting histone deacetylase enzymes (HDACs) regulates the immune response in several inflammatory disease models. The aim of the current study was to evaluate the effect of HDAC inhibition in the production of inflammatory cytokines in human monocyte-derived macrophages infected with DENV serotype 2 (DENV-2). To this end, human monocyte-derived macrophages (MDMs) were treated with valproic acid (VPA) before or after infection and the inflammatory cytokine concentration was quantified by flow cytometry. We found that infected MDMs secreted IL-8, IL-1b, IL-6, TNF-alpha, and IL-10, but not IL-12. Strikingly, treatment of infected cells with VPA had a differential and concentration-dependent effect on the production of specific cytokines without eliciting significant changes in cell viability. Using the highest concentration of VPA, a significant reduction in the production of all cytokines was observed. These results suggest that HDAC inhibition during DENV-2 infection could exert an important regulatory effect in the production of inflammatory cytokines, representing a significant advance in the design of novel therapeutic dengue treatments.

The high levels of dengue-virus (DENV) seroprevalence in areas where the Zika virus (ZIKV) is circulating and the cross-reactivity between these two viruses have raised concerns on the risk of increased ZIKV disease severity for patients with a history of previous DENV infections. To determine the role of DENV preimmunity in ZIKV infection, we analyzed the T- and B-cell responses against ZIKV in donors with or without previous DENV infection. Using peripheral blood mononuclear cells (PBMCs) from donors living in an endemic area in Colombia, we have identified, by interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) assay, most of the immunodominant ZIKV T-cell epitopes in the nonstructural (NS) proteins NS1, NS3, and NS5. Analyses of the T- and B-cell responses in the same donors revealed a stronger T-cell response against peptides conserved between DENV and ZIKV, with a higher level of ZIKV-neutralizing antibodies in DENV-immune donors in comparison with DENV-naïve donors. Strikingly, the potential for antibody-mediated enhancement of ZIKV infection was reduced in donors with sequential DENV and ZIKV infection in comparison with donors with DENV infection only. Altogether, these data suggest that individuals with DENV immunity present improved immune responses against ZIKV.

Summary It has been suggested that tumour cell lysis by gamma‐radiation induces a tumoral antigen release eliciting an immune response. It is not clear how a specific immune response in cervical cancer patients is developed after radiotherapy. This study is an attempt to investigate the role of the human papillomavirus type 16 (HPV‐16) E7‐specific T helper response before and after radiotherapy. Lymphocytes were isolated from 32 cervical cancer patients before and after radiotherapy and from 16 healthy women. They were stimulated for 12 hr with autologous HPV‐16 E7‐pulsed monocyte‐derived dendritic cells or directly with HPV‐16 E7 synthetic peptides: E751–70, E765–84 and E779–98. The cells were stained for CD4, CD69, intracellular interferon‐γ (IFN‐γ) and interleukin‐4 (IL‐4) cytokines and analysed by flow cytometry. A specific CD4+ CD69+ IFN‐γ+ immune response against HPV‐16 E779–98 peptide was observed in 10 of 14 patients (71·4%) after treatment, compared with 4 of 14 (28·5%) before radiotherapy (P = 0·039); however, this response was not associated with a successful clinical response. Before treatment, 5 of 31 patients showed a HPV‐16 E779–98‐specific T helper type 2 (Th2) response. Interestingly, this response was significantly associated with a decrease in disease‐free survival (P = 0·027). These results suggest that a Th2‐type cellular response could be useful as a predictor of recurrence and poor prognosis. An increase of the HPV‐specific immune response was observed after radiotherapy; however, it is not enough to control completely the disease after treatment. Our results support that the E7‐specific T‐cell IFN‐γ response in cervical cancer patients, rather than reflecting the host’s capability of controlling tumour growth, might be an indicator for disease severity.

Despite numerous efforts to identify the molecular and cellular effectors of the adaptive immunity that induce a long-lasting immunity against dengue or Zika virus infection, the specific mechanisms underlying such protective immunity remain largely unknown. One of the major challenges lies in the high level of dengue virus (DENV) seroprevalence in areas where Zika virus (ZIKV) is circulating. In the context of such a pre-existing DENV immunity that can exacerbate ZIKV infection and disease, and given the lack of appropriate treatment for ZIKV infection, there is an urgent need to develop an efficient vaccine against DENV and ZIKV. Notably, whereas several ZIKV vaccine candidates are currently in clinical trials, all these vaccine candidates have been designed to induce neutralizing antibodies as the primary mechanism of immune protection. Given the difficulty to elicit simultaneously high levels of neutralizing antibodies against the different DENV serotypes, and the potential impact of pre-existing subneutralizing antibodies induced upon DENV infection or vaccination on ZIKV infection and disease, additional or alternative strategies to enhance vaccine efficacy, through T cell immunity, are now being considered. In this review, we summarize recent discoveries about cross-reactive B and T cell responses against DENV and ZIKV and propose guidelines for the development of safe and efficient T cell vaccines targeting both viruses.