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Combination antiretroviral therapy (ART) suppresses human immunodeficiency virus (HIV) replication and improves immune function, but is unable to eradicate the virus. Therefore, development of an HIV cure has become one of the main priorities of the HIV research field. The main obstacle for an HIV cure is the formation of latent viral reservoirs, where the virus is able to \"hide\" despite decades of therapy, just to reignite active replication once therapy is stopped. Revealing HIV hiding places is thus central to HIV cure research, but the absence of markers of these reservoir cells greatly complicates the search for a cure. Identification of one or several marker(s) of latently infected cells would represent a significant step forward toward a better description of the cell types involved and improved understanding of HIV latency. Moreover, it could provide a \"handle\" for selective therapeutic targeting of the reservoirs. A number of cellular markers of HIV reservoir have recently been proposed, including immune checkpoint molecules, CD2, and CD30. CD32a is perhaps the most promising of HIV reservoir markers as it is reported to be associated with a very prominent enrichment in HIV DNA, although this finding has been challenged. In this review, we provide an update on the current knowledge about HIV reservoir markers. We specifically highlight studies that characterized markers of persistently infected cells in the lymphoid tissues.

The persistence of latently infected cells in patients under combinatory antiretroviral therapy (cART) is a major hurdle to HIV-1 eradication. Strategies to purge these reservoirs are needed and activation of viral gene expression in latently infected cells is one promising strategy. Bromodomain and Extraterminal (BET) bromodomain inhibitors (BETi) are compounds able to reactivate latent proviruses in a positive transcription elongation factor b (P-TEFb)-dependent manner. In this study, we tested the reactivation potential of protein kinase C (PKC) agonists (prostratin, bryostatin-1 and ingenol-B), which are known to activate NF-κB signaling pathway as well as P-TEFb, used alone or in combination with P-TEFb-releasing agents (HMBA and BETi (JQ1, I-BET, I-BET151)). Using in vitro HIV-1 post-integration latency model cell lines of T-lymphoid and myeloid lineages, we demonstrated that PKC agonists and P-TEFb-releasing agents alone acted as potent latency-reversing agents (LRAs) and that their combinations led to synergistic activation of HIV-1 expression at the viral mRNA and protein levels. Mechanistically, combined treatments led to higher activations of P-TEFb and NF-κB than the corresponding individual drug treatments. Importantly, we observed in ex vivo cultures of CD8+-depleted PBMCs from 35 cART-treated HIV-1+ aviremic patients that the percentage of reactivated cultures following combinatory bryostatin-1+JQ1 treatment was identical to the percentage observed with anti-CD3+anti-CD28 antibodies positive control stimulation. Remarkably, in ex vivo cultures of resting CD4+ T cells isolated from 15 HIV-1+ cART-treated aviremic patients, the combinations bryostatin-1+JQ1 and ingenol-B+JQ1 released infectious viruses to levels similar to that obtained with the positive control stimulation. The potent effects of these two combination treatments were already detected 24 hours post-stimulation. These results constitute the first demonstration of LRA combinations exhibiting such a potent effect and represent a proof-of-concept for the co-administration of two different types of LRAs as a potential strategy to reduce the size of the latent HIV-1 reservoirs.

Whether antiretroviral therapy (ART) is always completely suppressive, or HIV might continue to replicate at low levels despite ART in some people with HIV (PWH), is still debated. Here, we intensified the ART regimen by doubling dolutegravir (DTG) dosage and investigated the impact of this strategy on HIV blood and tissue reservoirs, immune activation, and inflammation. Twenty HIV-infected adults, who had received a triple ART consisting of 50 mg DTG/600 mg abacavir/300 mg lamivudine pre-intensification and had been suppressed on ART for at least 2 years, were enrolled in a phase 2 randomized clinical trial ( https://clinicaltrials.gov/ identifier: NCT05351684). Half of them received an additional 50 mg of DTG for a period of 84 days. As expected, plasma and tissue DTG concentrations significantly increased during the study period in the intensified group but not in the control group. Accordingly, significant decreases in total HIV DNA, intact HIV DNA, and cell-associated unspliced (US) HIV RNA in peripheral blood mononuclear cells, as well as in the US RNA/total DNA ratio, were observed in the intensified group but not in the control group. Intensification also modestly reduced markers of immune activation and exhaustion but had no measurable impact on systemic or tissue inflammation. Together with this, intensification resulted in a temporary decrease in the CD4/CD8 ratio that returned to baseline by day 84. Our results strongly suggest that the pre-intensification ART regimen was not completely suppressive. If confirmed in larger clinical trials, these results could have an impact on the clinical management of PWH and HIV curative strategies.

Background: Zoonotic risks in exposed students are poorly documented in Belgium. According to the literature, even though human tick-borne encephalitis (TBE) infection risk has increased significantly in southern Belgium, no previous human serological survey has demonstrated specific antibodies directed at TBE virus. Methods and principal findings: The aim of this paper was to perform a representative serological survey on sera involving students at the University of Liege, in the southern part of Belgium, to discover possible exposure to TBEV. A total of 207 sera samples were randomly chosen and analyzed using ELISA IgM (with 1 positive student out of 207) and ELISA IgG (with 10 positive students out of 207), subsequent serial immunofluorescence antibody testing (IFAT) IgG (with 8 positive students out of 10 positive in ELISA IgG) and serial IFAT IgM (with 1 negative student out of 1 positive in ELISA IgM), and confirmatory tests, i.e., 50% and 90% plaque reduction neutralization tests (PRNTs) (1 strongly positive student out of 8 positive in IFAT). Conclusions and significance: The exposure of students from the southern part of Belgium (area with increasing risk) to TBEV was assessed for the first time. Antibodies against TBEV could only be demonstrated in 1 out of 207 students. This finding contributes to better decision-making in public health and prevention and management of tick-borne diseases in the context of climate change. Awareness among all students should be prioritized, with prevention measures against tick bites, particularly during forest and recreational activities contributing to risk, to maintain the current low seroprevalence levels.

Background Varying from 30% to 50% depending on the study, the high rate of inappropriate antimicrobial prescriptions is a major concern. These inappropriate prescriptions contribute to antibiotic resistance and associated morbidity and mortality. Prospective audit and feedback interventions is one of the core strategies recommended by the Infectious Diseases Society of America to improve antibiotic use. In line with this guidance, this approach was selected to evaluate piperacillin-tazobactam (PTZ) use within our institution. Methods A prospective audit of PTZ prescribing was conducted over an 11-week period at the CHU of Liège. Prescriptions were reviewed weekly by an infectious diseases specialist and a clinical hospital pharmacist. The primary outcome was the appropriateness of PTZ prescriptions across three main evaluation criteria -indication, spectrum and duration- and one minor criterion -notification of the indication in the medical records-. The secondary outcome was to identify potential drivers of inappropriate prescribing. Interventions involved antibiotic discontinuation, de-escalation, oral step-down therapy and optimizing the pharmacokinetic and pharmacodynamic (PK/PD) profile. Results Overall, 91.8% of the prescriptions were deemed appropriate for indication, 74.5% for spectrum, and 50% for duration. Notification was adequate in 65.5% of cases. However, most prescriptions were empirical (nearly 90%). Regarding stewardship interventions, broad-spectrum antibiotics were discontinued or de-escalated in 33.6% and 19.1% of cases, respectively, with intravenous-to-oral switch and PK/PD optimization suggested in 17.3% and 11.8% of cases. Our study identified several statistically significant determinants of inappropriate antibiotic use, including the type of care unit and the Charlson Comorbidity Index. Conclusions Our findings point out the role of an antimicrobial stewardship program in improving antibiotic use, especially in surgical units where inappropriate indication and poor notification were most common. Importantly, antibiotic treatment duration remains problematic across all hospital units. By linking patient characteristics to outcomes, our study identifies key drivers of inappropriate use, which could be further confirmed and refined in future research.

SARS-CoV-2 remains a worldwide emergency. While vaccines have been approved and are widely administered, there is an ongoing debate whether children should be vaccinated or prioritized for vaccination. Therefore, in order to mitigate the spread of more transmissible SARS-CoV-2 variants among children, the use of non-pharmaceutical interventions is still warranted. We investigate the impact of different testing strategies on the SARS-CoV-2 infection dynamics in a primary school environment, using an individual-based modelling approach. Specifically, we consider three testing strategies: (1) symptomatic isolation , where we test symptomatic individuals and isolate them when they test positive, (2) reactive screening , where a class is screened once one symptomatic individual was identified, and (3) repetitive screening , where the school in its entirety is screened on regular time intervals. Through this analysis, we demonstrate that repetitive testing strategies can significantly reduce the attack rate in schools, contrary to a reactive screening or a symptomatic isolation approach. However, when a repetitive testing strategy is in place, more cases will be detected and class and school closures are more easily triggered, leading to a higher number of school days lost per child. While maintaining the epidemic under control with a repetitive testing strategy, we show that absenteeism can be reduced by relaxing class and school closure thresholds.

Opportunistic viral infections of the central nervous system represent a significant cause of morbidity and mortality among an increasing number of immunocompromised patients. Since antiviral treatments are usually poorly effective, the prognosis generally relies on the ability to achieve timely immune reconstitution. Hence, strategies aimed at reinvigorating antiviral immune activity have recently emerged. Among these, virus-specific T-cells are increasingly perceived as a principled and valuable tool to treat opportunistic viral infections. Here we briefly discuss how to develop and select virus-specific T-cells, then review their main indications in central nervous system infections, including progressive multifocal leukoencephalopathy, CMV infection, and adenovirus infection. We also discuss their potential interest in the treatment of progressive multiple sclerosis, or EBV-associated central nervous system inflammatory disease. We finish with the key future milestones of this promising treatment strategy.

Despite effective antiretroviral therapy (ART), people with HIV (PWH) experience persistent immune activation and inflammation, increasing the risk of non-AIDS-related comorbidities. The contribution of the HIV reservoir to this chronic inflammatory state remains debated. Understanding the relationship between HIV persistence, immune activation, and inflammation is crucial for optimizing long-term therapeutic strategies. This study assessed HIV persistence, immune activation, and systemic inflammation in 49 PWH treated with the same dolutegravir-based triple ART regimen. HIV reservoir size and activity were evaluated by measuring total HIV DNA in peripheral blood mononuclear cells (PBMCs) and rectal tissue, cell-associated (CA) unspliced (US) HIV RNA, and residual viremia. Over 20 inflammatory biomarkers, including sCD14, IL-6, TNF-α, and CXCL10, were analyzed, along with comprehensive immune profiling using a 26-color spectral flow cytometry panel. Clinical parameters such as age, nadir CD4 count, and co-infections were also considered. Our findings showed a limited association between HIV persistence markers and systemic inflammation or immune activation. Compared to previous studies, participants had lower reservoir sizes and transcriptional activity, likely due to early ART initiation and prolonged suppression. Immune preservation was evident, with high CD4/CD8 ratios and reduced activation markers. These results challenge the idea that the HIV reservoir is the primary driver of chronic inflammation in PWH on a dolutegravir-based long-term ART. Instead, the reservoir may evolve toward a more transcriptionally silent and defective state, reducing its impact on systemic immune activation.

While many studies have used the Health Belief Model (HBM) to understand vaccine intention, none claim to have used serial mediation to understand the relationship between HBM dimensions and COVID-19 vaccine intention. This study developed a serial mediation model to assess the direct and indirect effects of the latent HBM dimensions on COVID-19 primary vaccine intention. A cross-sectional study: from 01 April to 10 June 2021, a self-administered online questionnaire on vaccine intention against COVID-19 was distributed to staff and students at the University of Liège (Belgium). Direct and indirect effects of the HBM dimensions (perceived susceptibility, severity, benefits, barriers, self-efficacy and cues to action) on vaccine intention (score 0-100) were assessed with serial mediation models. Actually, each permutation of the latent HBM dimensions, i.e., each causal chain, was assessed using partial least squares path modelling (PLS-PM) according to the order of the HBM dimensions in that particular chain. The sample was made up of 1256 participants. The final model revealed that the causal chain with the lowest Bayesian Information Criterion (BIC) value was barriers (Effect estimation (CI95%): -0.09 (-0.15 - -0.03)) ↘ severity (-0.13 (-0.20 - -0.07)) ↘ low self-efficacy (0.20 (0.15-0.25)) ↘ low susceptibility (-0.55 (-0.60 - -0.51)) ↘ vaccine intention (outcome). This revealed a significant indirect and direct effect (-0.20 (-0.25 - -0.15)) between barriers and vaccine intention. The results demonstrated that perceived barriers are a key determinant in COVID-19 primary vaccine intention. Public health practitioners need to prioritise messaging that addresses the barriers reducing vaccine intention to enable individuals to make an informed choice. These messages could form part of a mass communication campaign aimed at hesitant individuals, with evidence-based information about vaccine safety a priority in order to establish a climate of trust.

Understanding and measuring the individual level of immune protection and its persistence at both humoral and cellular levels after SARS-CoV-2 vaccination is mandatory for the management of the vaccination booster campaign. Our prospective study was designed to assess the immunogenicity of the BNT162b2 mRNA vaccine in triggering the cellular and humoral immune response in healthcare workers up to 12 months after the initial vaccination, with one additional boosting dose between 6 and 12 months. This prospective study enrolled 208 healthcare workers (HCWs) from the Liège University Hospital (CHU) of Liège in Belgium. Participants received two doses of BioNTech/Pfizer COVID-19 vaccine (BNT162b2) and a booster dose 6-12 months later. Fifty participants were SARS-CoV-2 experienced and 158 were naïve before the vaccination. Blood sampling was performed at the day of the first (T0) and second (T1) vaccine doses administration, then at 2 weeks (T2), 4 weeks (T3), 6 months (T4) and 12 months (T5) after the second dose. Between T4 and T5, participants also got the third boosting vaccine dose. A total of 1145 blood samples were collected. All samples were tested for the presence of anti-Spike antibodies, using the DiaSorin LIAISON SARS-CoV-2 Trimeric S IgG assay, and for anti-Nucleocapsid antibodies, using Elecsys anti-SARS-CoV-2 assay​​. Neutralizing antibodies against the SARS-CoV-2 Wuhan-like variant strain were quantified in all samples using a Vero E6 cell-based neutralization assay. Cell-mediated immune response was evaluated at T4 and T5 on 80 and 55 participants, respectively, by measuring the secretion of IFN-γ on peripheral blood lymphocytes using the QuantiFERON Human IFN-γ SARS-CoV-2, from Qiagen. We analyzed separately the naïve and experienced participants. We found that anti-spike antibodies and neutralization capacity levels were significantly higher in SARS-CoV-2 experienced HCWs compared to naïve HCWs at all time points analyzed except the one after boosting dose. Cellular immune response was also higher in experienced HCWs six months following vaccination. Besides the impact of SARS-CoV-2 infection history on immune response to BNT162b2 mRNA vaccine, we observed a significant negative association between age and persistence of humoral response. The booster dose induced an increase in humoral and cellular immune responses, particularly in naive individuals. Breakthrough infections resulted in higher cellular and humoral responses after the booster dose. Our data strengthen previous findings demonstrating that immunization through vaccination combined with natural infection is better than 2 vaccine doses immunization or natural infection alone. The benefit of the booster dose was greater in naive individuals. It may have implications for personalizing mRNA vaccination regimens used to prevent severe COVID-19 and reduce the impact of the pandemic on the healthcare system. More specifically, it may help prioritizing vaccination, including for the deployment of booster doses.