Arthropod-borne viruses pose a major threat to global public health. Thus, innovative strategies for their control and prevention are urgently needed. Here, we exploit the natural capacity of viruses to generate defective viral genomes (DVGs) to their detriment. While DVGs have been described for most viruses, identifying which, if any, can be used as therapeutic agents remains a challenge. We present a combined experimental evolution and computational approach to triage DVG sequence space and pinpoint the fittest deletions, using Zika virus as an arbovirus model. This approach identifies fit DVGs that optimally interfere with wild-type virus infection. We show that the most fit DVGs conserve the open reading frame to maintain the translation of the remaining non-structural proteins, a characteristic that is fundamental across the flavivirus genus. Finally, we demonstrate that the high fitness DVG is antiviral in vivo both in the mammalian host and the mosquito vector, reducing transmission in the latter by up to 90%. Our approach establishes the method to interrogate the DVG fitness landscape, and enables the systematic identification of DVGs that show promise as human therapeutics and vector control strategies to mitigate arbovirus transmission and disease.

Malnourishment, specifically overweight/obesity and undernourishment, affects more than 2.5 billion people worldwide, with the number affected ever-increasing. Concurrently, emerging viral diseases, particularly those that are mosquito-borne, have spread dramatically in the past several decades, culminating in outbreaks of several viruses worldwide. Both forms of malnourishment are known to lead to an aberrant immune response, which can worsen disease outcomes and reduce vaccination efficacy for viral pathogens such as influenza and measles. Given the increasing rates of malnutrition and spread of arthropod-borne viruses (arboviruses), there is an urgent need to understand the role of host nutrition on the infection, virulence, and transmission of these viruses. To address this gap in knowledge, we infected lean, obese, and undernourished mice with arthritogenic arboviruses from the genus Alphavirus and assessed morbidity, virus replication, transmission, and evolution. Obesity and undernourishment did not consistently influence virus replication in the blood of infected animals except for reductions in virus in obese mice late in infection. However, morbidity was increased in obese mice under all conditions. Using Mayaro virus (MAYV) as a model arthritogenic alphavirus, we determined that both obese and undernourished mice transmit virus less efficiently to mosquitoes than control (lean) mice. In addition, viral genetic diversity and replicative fitness were reduced in virus isolated from obese compared to lean controls. Taken together, nutrition appears to alter the course of alphavirus infection and should be considered as a critical environmental factor during outbreaks. Over- and undernutrition, collectively known as malnutrition, affect over 2.5 billion people worldwide. Associations between malnutrition and mosquito-borne virus infection and resulting disease have been identified in epidemiological studies but have not been explored in controlled studies. Here, we infect obese or undernourished mice with different arthritis inducing viruses in the genus Alphavirus and measure disease symptoms, viral replication, transmission, and evolution. We found that markers of disease, namely weight loss and footpad swelling, were increased in obese mice. We also found that replication differences between mice fed different diets were minimal except late in infection for obese mice when levels of virus dropped significantly. When mosquitoes were allowed to feed on mice fed different diets, we observed reduced infection and transmission rates, depending on the diet. Finally, we found reduced genetic diversity and replicative fitness of virus isolated from obese mice. This study provides insights into the influence of nutrition on alphavirus pathogenesis and evolution.

Defective viral genomes (DVGs) are truncated and/or rearranged viral genomes produced during virus replication. Described in many RNA virus families, some of them have interfering activity on their parental virus and/or strong immunostimulatory potential, and are being considered in antiviral approaches. Chikungunya virus (CHIKV) is an alphavirus transmitted by Aedes spp. that infected millions of humans in the last 15 years. Here, we describe the DVGs arising during CHIKV infection in vitro in mammalian and mosquito cells, and in vivo in experimentally infected Aedes aegypti mosquitoes. We combined experimental and computational approaches to select DVG candidates most likely to have inhibitory activity and showed that, indeed, they strongly interfere with CHIKV replication both in mammalian and mosquito cells. We further demonstrated that some DVGs present broad-spectrum activity, inhibiting several CHIKV strains and other alphaviruses. Finally, we showed that pre-treating Aedes aegypti with DVGs prevented viral dissemination in vivo.

Historically, women have been shown to underestimate their abilities, while men often assess themselves more accurately or overestimate. This study aims to determine self-assessment accuracy during online Objective Structured Clinical Examinations (OSCEs) according to gender. A prospective study was conducted among fourth-year medical students at Paris Cité University during faculty training OSCEs, utilizing Zoom® software for remote participation. Students and evaluators assessed performances using 5-point Likert scales for medical knowledge, interpersonal skills, and overall performance. Additionally, students predicted their grade out of twenty. The assessment covered three independent stations. This study included 259 medical students (177 women, 81 men, one non-binary (excluded from further analyses)) evaluated by 130 physicians. Evaluator scores did not differ according to students’ gender (total score out of 20: men: 10.25 ± 3.45, women: 10.23 ± 3.44 p = 0.817) nor students’ self-assessments (total score out of 20: men: 11.22 ± 3.02, women: 11.00 ± 3.03; p = 0.466) whatever the domains and stations (all p > 0.05). The difference (delta) between self-assessment and evaluator scores for medical knowledge (men: 0.73 ± 1.00, women: 0.64 ± 1.02; p = 0.296), interpersonal skills (men: 1.02 ± 1.06, women: 0.93 ± 1.09; p = 0.296), and total score (men: 0.98 ± 3.41, women: 0.68 ± 3.42; p = 0.296) showed no gender differences. Further analysis categorized students based on their self-assessment accuracy, revealing that both men and women displayed a high ratio of accurate self-assessments (78.1% for overall performance across all stations), with minimal overestimation observed in both genders (20.9% for overall performance across all stations). Instances of overestimation or underestimation were rare and not consistent over the 3 stations, indicating that such misjudgments are likely situational rather than inherent traits. This study reveals similar self-assessment accuracy according to gender in online training OSCEs suggesting a shift towards gender-equitable self-perceptions among medical students compared to previous studies. Research remains necessary to corroborate these results and explore the underlying factors contributing to this shift in self-perception.

Objective: The aim of this study was to assess the prevalence of cytomegalovirus (CMV) viremia in HIV-positive patients starting antiretroviral therapy (ART) and to evaluate its impact on clinical outcomes. Design: A retrospective analysis of four clinical trials (INSIGHT FIRST, SMART, START, and ANRS REFLATE TB). Methods: Stored plasma samples from participants were used to measure CMV viremia at baseline prior to initiating ART and at visits through 1 year of follow-up after ART initiation. CMV viremia was measured centrally using a quantitative PCR assay. Within FIRST, associations of CMV viremia at baseline and through 8 months of ART were examined with a composite clinical outcome of AIDS, serious non-AIDS events, or death using Cox proportional hazards regression. Results: Samples from a total of 3176 participants, 1169 from FIRST, 137 from ANRS REFLATE TB, 54 from SMART, and 1816 from START were available with baseline CMV viremia prevalence of 17, 26, 0, and 1%, respectively. Pooled across trials, baseline CMV viremia was associated with low CD4⁺ T-cell counts and high HIV RNA levels. In FIRST, CMV viremia was detected in only 5% of participants between baseline and month 8. After adjustment for CD4⁺ T-cell count and HIV RNA levels, hazard ratios for risk of clinical outcomes was 1.15 (0.86–1.54) and 2.58 (1.68–3.98) in FIRST participants with baseline and follow-up CMV viremia, respectively. Conclusion: Baseline CMV viremia in HIV-positive patients starting ART is associated with advanced infection and only persistent CMV viremia after ART initiation is associated with a higher risk of morbidity and mortality.

Diphtheria is a re-emerging disease in resource-rich settings. We here report three cases of cutaneous diphtheria diagnosed and managed in our infectious disease department and discuss the determinants of its re-emergence. Migration, travel and vaccine skepticism are key factors not only for diphtheria re-emergence, but for the future of most preventable diseases.