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Research and Clinical Application of Adenovirus (AdV), 2nd Edition
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Research and Clinical Application of Adenovirus (AdV), 2nd Edition

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Human Virology and Viral Diseases".

Deadline for manuscript submissions: closed (31 October 2024) | Viewed by 23789

Special Issue Editor

Dr. Julia Davydova

E-Mail Website
Guest Editor
Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA
Interests: adenovirus; oncolytic; cancer; models; gene; therapy; delivery; translation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The concept behind using viruses to fight human diseases is very straightforward: for millions of years, they have been delivering their genes to different types of mammalian and human cells. Indeed, virus-based gene therapy is a growing area of modern medicine as viruses have the potential to overcome the limitations of conventional therapeutic approaches.

Adenovirus (AdV) is one of the most versatile viral backbones with applications ranging from gene delivery and treatment of monogenic diseases to vaccination and cancer therapy. Adenoviruses can target a broad spectrum of both dividing and non-dividing cells, do not integrate into host DNA, have high in vivo transduction capacity, and are well characterized, thereby allowing for countless modifications of their genetic structure. The first AdV-based therapy took place in 1956, when 30 patients with cervical carcinoma were treated with adenoidal–pharyngeal–conjunctival virus, now known as an adenovirus. After a turbulent past full of both medical achievements and failures, the stigma related to adenovirus has been gradually replaced by the wide acceptance of the feasibility and safety of AdV-based therapeutics. It is difficult to overestimate the value of AdV during the COVID-19 pandemic as, to date, AdV represents the most effective viral vector platform for anti-SARS-CoV-2 vaccines. The recent clinical successes have also demonstrated the promise of tumor-selective, infectivity-improved oncolytic adenoviruses for cancer gene therapy and highlighted their role in inducing anticancer immunity.

In this second special issue, we discuss the latest advances in adenovirus research and how AdV can be used to treat human disease.

Dr. Julia Davydova
Guest Editor

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • adenovirus
  • gene
  • therapy
  • cancer
  • oncolytic
  • vaccine
  • delivery

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Related Special Issues

Published Papers (11 papers)

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Research

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14 pages, 2129 KiB  
Article
Longitudinal Monitoring of the Effects of Anti-Adenoviral Treatment Regimens in a Permissive In Vivo Model
by Ann E. Tollefson, Anna Cline-Smith, Jacqueline F. Spencer, Baoling Ying, Dawn M. Reyna, Elke Lipka, Scott H. James and Karoly Toth
Viruses 2024, 16(8), 1200; https://doi.org/10.3390/v16081200 - 26 Jul 2024
Viewed by 583
Abstract
Adenovirus infections of immunocompromised patients can cause life-threatening disseminated disease. While there are presently no drugs specifically approved to treat these infections, there are several compounds that showed efficacy against adenovirus in preclinical studies. For any such compound, low toxicity is an essential [...] Read more.
Adenovirus infections of immunocompromised patients can cause life-threatening disseminated disease. While there are presently no drugs specifically approved to treat these infections, there are several compounds that showed efficacy against adenovirus in preclinical studies. For any such compound, low toxicity is an essential requirement. As cumulative drug effects can accentuate pathology, especially in patients with other morbidities, it is important to limit antiviral exposure to what is absolutely necessary. This is achievable by monitoring the virus burden of the patients and administering antivirals to suppress virus replication to a non-pathogenic level. We modeled such a system using Syrian hamsters infected with a replication-competent adenovirus vector, in which luciferase expression is coupled to virus replication. We found that virus replication could be followed in vivo in the same animal by repeated measurement of luciferase expression. To test the utility of an interrupted treatment regimen, we used NPP-669 and valganciclovir, two antiviral compounds with high and moderate anti-adenoviral efficacy, respectively. We found that short-term treatment of adenovirus-infected hamsters at times of peak virus replication can prevent virus-associated pathology. Thus, we believe that this animal model can be used to model different treatment regimens for anti-adenoviral compounds. Full article
(This article belongs to the Special Issue Research and Clinical Application of Adenovirus (AdV), 2nd Edition)
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9 pages, 430 KiB  
Article
Influence of Seropositivity against Adenovirus-36 on the Risk of Obesity and Insulin Resistance in the Child Population of Southern Chile
by Roberto Brito, Jorge Sapunar, Nicolás Aguilar-Farías, Juan Navarro-Riquelme, Monica Pavez, Mario Hiroyuki Hirata and Alvaro Cerda
Viruses 2024, 16(6), 995; https://doi.org/10.3390/v16060995 - 20 Jun 2024
Viewed by 918
Abstract
Background: Previous infection with Adenovirus-36 (HAdv-D36) has been associated with adipogenesis and glycemic regulation in cell culture and animal models. In humans, HAdv-D36 antibodies correlate with increased obesity risk yet paradoxically enhance glycemic control across various demographics. This study assesses the association of [...] Read more.
Background: Previous infection with Adenovirus-36 (HAdv-D36) has been associated with adipogenesis and glycemic regulation in cell culture and animal models. In humans, HAdv-D36 antibodies correlate with increased obesity risk yet paradoxically enhance glycemic control across various demographics. This study assesses the association of HAdv-D36 seropositivity with obesity, lipid, and glycemic profiles among school-aged children. Methods: We evaluated 208 children aged 9–13, categorized by BMI z-scores into normal weight (−1 to +1), overweight (+1 to +2), and obese (>+3). Assessments included anthropometry, Tanner stage for pubertal development, and biochemical tests (relating to lipids, glucose, and insulin), alongside HAdv-D36 seropositivity checked via ELISA. Insulin resistance was gauged using Chilean pediatric criteria. Results: The cohort displayed a high prevalence of overweight/obesity. HAdv-D36 seropositivity was 5.4%, showing no correlation with nutritional status. Additionally, no link between HAdv-D36 seropositivity and lipid levels was observed. Notably, insulin levels and HOMA-RI were significantly lower in HAdv-D36 positive children (p < 0.001). No cases of insulin resistance were reported in the HAdv-D36 (+) group in our population. Conclusions: HAdv-D36 seropositivity appears to decrease insulin secretion and resistance, aligning with earlier findings. However, no association with obesity development was found in the child population of southern Chile. Full article
(This article belongs to the Special Issue Research and Clinical Application of Adenovirus (AdV), 2nd Edition)
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16 pages, 4401 KiB  
Article
High-Frequency Recombination of Human Adenovirus in Children with Acute Respiratory Tract Infections in Beijing, China
by Fangming Wang, Ri De, Zhenzhi Han, Yanpeng Xu, Runan Zhu, Yu Sun, Dongmei Chen, Yutong Zhou, Qi Guo, Dong Qu, Ling Cao, Liying Liu and Linqing Zhao
Viruses 2024, 16(6), 828; https://doi.org/10.3390/v16060828 - 23 May 2024
Viewed by 1121
Abstract
Recombination events in human adenovirus (HAdV) have led to some new highly pathogenic or infectious types. It is vital to monitor recombinant HAdVs, especially in children with acute respiratory tract infections (ARIs). In the retrospective study, HAdV positive specimens were collected from pediatric [...] Read more.
Recombination events in human adenovirus (HAdV) have led to some new highly pathogenic or infectious types. It is vital to monitor recombinant HAdVs, especially in children with acute respiratory tract infections (ARIs). In the retrospective study, HAdV positive specimens were collected from pediatric patients with ARIs during 2015 to 2021, then typed by sequence analysis of the penton base, hexon and fiber gene sequence. For those with inconsistent typing results, a modified method with species-specific primer sets of a fiber gene sequence was developed to distinguish co-infections of different types from recombinant HAdV infections. Then, plaque assays combined with meta-genomic next-generation sequencing (mNGS) were used to reveal the HAdV genomic characteristics. There were 466 cases positive for HAdV DNA (2.89%, 466/16,097) and 350 (75.11%, 350/466) successfully typed with the most prevalent types HAdV-B3 (56.57%, 198/350) and HAdV-B7 (32.00%, 112/350), followed by HAdV-C1 (6.00%, 21/350). Among 35 cases (7.51%, 35/466) with inconsistent typing results, nine cases were confirmed as co-infections by different types of HAdVs, and 26 cases as recombinant HAdVs in six genetic patterns primarily clustered to species C (25 cases) in pattern 1–5, or species D (1 case) in pattern 6. The novel recombinant HAdV of species D was identified with multiple recombinant events among HAdV-D53, HAdV-D64, and HAdV-D8, and officially named as HAdV-D115. High-frequency recombination of HAdVs in six genetic recombination patterns were identified among children with ARIs in Beijing. Specifically, there is a novel Adenovirus D human/CHN/S8130/2023/115[P22H8F8] designed as HAdV D115. Full article
(This article belongs to the Special Issue Research and Clinical Application of Adenovirus (AdV), 2nd Edition)
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13 pages, 2321 KiB  
Article
DMSO and Its Role in Differentiation Impact Efficacy of Human Adenovirus (HAdV) Infection in HepaRG Cells
by Katharina Hofmann, Samuel Hofmann, Franziska Weigl, Julia Mai and Sabrina Schreiner
Viruses 2024, 16(4), 633; https://doi.org/10.3390/v16040633 - 19 Apr 2024
Viewed by 1528
Abstract
Differentiated HepaRG cells are popular in vitro cell models for hepatotoxicity studies. Their differentiation is usually supported by the addition of dimethyl sulfoxide (DMSO), an amphipathic solvent widely used in biomedicine, for example, in potential novel therapeutic drugs and cryopreservation of oocytes. Recent [...] Read more.
Differentiated HepaRG cells are popular in vitro cell models for hepatotoxicity studies. Their differentiation is usually supported by the addition of dimethyl sulfoxide (DMSO), an amphipathic solvent widely used in biomedicine, for example, in potential novel therapeutic drugs and cryopreservation of oocytes. Recent studies have demonstrated drastic effects, especially on epigenetics and extracellular matrix composition, induced by DMSO, making its postulated inert character doubtful. In this work, the influence of DMSO and DMSO-mediated modulation of differentiation on human adenovirus (HAdV) infection of HepaRG cells was investigated. We observed an increase in infectivity of HepaRG cells by HAdVs in the presence of 1% DMSO. However, this effect was dependent on the type of medium used for cell cultivation, as cells in William’s E medium showed significantly stronger effects compared with those cultivated in DMEM. Using different DMSO concentrations, we proved that the impact of DMSO on infectability was dose-dependent. Infection of cells with a replication-deficient HAdV type demonstrated that the mode of action of DMSO was based on viral entry rather than on viral replication. Taken together, these results highlight the strong influence of the used cell-culture medium on the performed experiments as well as the impact of DMSO on infectivity of HepaRG cells by HAdVs. As this solvent is widely used in cell culture, those effects must be considered, especially in screening of new antiviral compounds. Full article
(This article belongs to the Special Issue Research and Clinical Application of Adenovirus (AdV), 2nd Edition)
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13 pages, 780 KiB  
Article
Effect of Human Adenovirus 36 on Response to Metformin Monotherapy in Obese Mexican Patients with Type 2 Diabetes: A Prospective Cohort Study
by José Carlos Tapia-Rivera, Héctor Eduardo Mendoza-Jaramillo, Christian Octavio González-Villaseñor, Mario Ramirez-Flores, José Alonso Aguilar-Velazquez, Andres López-Quintero, Edsaúl Emilio Pérez-Guerrero, María de los Ángeles Vargas-Rodriguez, Itzae Adonai Gutiérrez-Hurtado and Erika Martínez-López
Viruses 2023, 15(7), 1514; https://doi.org/10.3390/v15071514 - 7 Jul 2023
Cited by 2 | Viewed by 2752
Abstract
Human adenovirus 36 (HAdV-36) has been associated with obesity and changes in glucose and lipid metabolism. The virus has been reported to increase insulin sensitivity and paradoxically promote weight gain. Because of its effects on metabolism, infection with the virus could alter the [...] Read more.
Human adenovirus 36 (HAdV-36) has been associated with obesity and changes in glucose and lipid metabolism. The virus has been reported to increase insulin sensitivity and paradoxically promote weight gain. Because of its effects on metabolism, infection with the virus could alter the response to several drugs used to treat type 2 diabetes (DM2), such as metformin. The aim of this study was to test whether HAdV-36 affects the response to metformin in a group of obese patients with DM2. Methods: In a prospective cohort study, 103 obese patients with newly diagnosed DM2 were divided into two groups based on their HAdV-36 seropositivity (+HAdV-36 and −HAdV-36). Weight, glucose, cholesterol, triglycerides, body mass index, body fat percentage, and waist and hip circumference were measured and compared in both groups at baseline and after 45 days of metformin treatment. Results: Only glucose was significantly lower in the +HAdV-36 group at baseline, while all other variables were similar between the two study groups. After 45 days of follow-up, it was observed that the effect of metformin did not differ between the groups, but the variables improved significantly after treatment. Conclusions: In this study, we did not find that HAdV-36 had an effect on the response to metformin in obese patients with DM2. Full article
(This article belongs to the Special Issue Research and Clinical Application of Adenovirus (AdV), 2nd Edition)
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Review

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21 pages, 1359 KiB  
Review
Clinical Application of Adenovirus (AdV): A Comprehensive Review
by Md. Salauddin, Sukumar Saha, Md. Golzar Hossain, Kenji Okuda and Masaru Shimada
Viruses 2024, 16(7), 1094; https://doi.org/10.3390/v16071094 - 8 Jul 2024
Viewed by 2631
Abstract
Adenoviruses are non-enveloped DNA viruses that cause a wide range of symptoms, from mild infections to life-threatening diseases in a broad range of hosts. Due to the unique characteristics of these viruses, they have also become a vehicle for gene-transfer and cancer therapeutic [...] Read more.
Adenoviruses are non-enveloped DNA viruses that cause a wide range of symptoms, from mild infections to life-threatening diseases in a broad range of hosts. Due to the unique characteristics of these viruses, they have also become a vehicle for gene-transfer and cancer therapeutic instruments. Adenovirus vectors can be used in gene therapy by modifying wild-type viruses to render them replication-defective. This makes it possible to swap out particular viral genes for segments that carry therapeutic genes and to employ the resultant vector as a means of delivering genes to specified tissues. In this review, we outline the progressive development of adenovirus vectors, exploring their characteristics, genetic modifications, and range of uses in clinical and preclinical settings. A significant emphasis is placed on their crucial role in advancing gene therapy, cancer therapy, immunotherapy, and the latest breakthroughs in vaccine development for various diseases. Full article
(This article belongs to the Special Issue Research and Clinical Application of Adenovirus (AdV), 2nd Edition)
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16 pages, 967 KiB  
Review
C-Terminal Binding Protein: Regulator between Viral Infection and Tumorigenesis
by Meihui Huang, Yucong Li, Yuxiao Li and Shuiping Liu
Viruses 2024, 16(6), 988; https://doi.org/10.3390/v16060988 - 19 Jun 2024
Viewed by 992
Abstract
C-terminal binding protein (CtBP), a transcriptional co-repressor, significantly influences cellular signaling, impacting various biological processes including cell proliferation, differentiation, apoptosis, and immune responses. The CtBP family comprises two highly conserved proteins, CtBP1 and CtBP2, which have been shown to play critical roles in [...] Read more.
C-terminal binding protein (CtBP), a transcriptional co-repressor, significantly influences cellular signaling, impacting various biological processes including cell proliferation, differentiation, apoptosis, and immune responses. The CtBP family comprises two highly conserved proteins, CtBP1 and CtBP2, which have been shown to play critical roles in both tumorigenesis and the regulation of viral infections. Elevated CtBP expression is noted in various tumor tissues, promoting tumorigenesis, invasiveness, and metastasis through multiple pathways. Additionally, CtBP’s role in viral infections varies, exhibiting differing or even opposing effects depending on the virus. This review synthesizes the advances in CtBP’s function research in viral infections and virus-associated tumorigenesis, offering new insights into potential antiviral and anticancer strategies. Full article
(This article belongs to the Special Issue Research and Clinical Application of Adenovirus (AdV), 2nd Edition)
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13 pages, 2032 KiB  
Review
Integrin-Targeting Strategies for Adenovirus Gene Therapy
by Glen R. Nemerow
Viruses 2024, 16(5), 770; https://doi.org/10.3390/v16050770 - 13 May 2024
Viewed by 1773
Abstract
Numerous human adenovirus (AdV) types are endowed with arginine–glycine–aspartic acid (RGD) sequences that enable them to recognize vitronectin-binding (αv) integrins. These RGD-binding cell receptors mediate AdV entry into host cells, a crucial early step in virus infection. Integrin interactions with adenoviruses not only [...] Read more.
Numerous human adenovirus (AdV) types are endowed with arginine–glycine–aspartic acid (RGD) sequences that enable them to recognize vitronectin-binding (αv) integrins. These RGD-binding cell receptors mediate AdV entry into host cells, a crucial early step in virus infection. Integrin interactions with adenoviruses not only initiate receptor-mediated endocytosis but also facilitate AdV capsid disassembly, a prerequisite for membrane penetration by AdV protein VI. This review discusses fundamental aspects of AdV–host interactions mediated by integrins. Recent efforts to re-engineer AdV vectors and non-viral nanoparticles to target αv integrins for bioimaging and the eradication of cancer cells will also be discussed. Full article
(This article belongs to the Special Issue Research and Clinical Application of Adenovirus (AdV), 2nd Edition)
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18 pages, 1966 KiB  
Review
Advances of Recombinant Adenoviral Vectors in Preclinical and Clinical Applications
by Luca Scarsella, Eric Ehrke-Schulz, Michael Paulussen, Serge C. Thal, Anja Ehrhardt and Malik Aydin
Viruses 2024, 16(3), 377; https://doi.org/10.3390/v16030377 - 28 Feb 2024
Cited by 4 | Viewed by 3037
Abstract
Adenoviruses (Ad) have the potential to induce severe infections in vulnerable patient groups. Therefore, understanding Ad biology and antiviral processes is important to comprehend the signaling cascades during an infection and to initiate appropriate diagnostic and therapeutic interventions. In addition, Ad vector-based vaccines [...] Read more.
Adenoviruses (Ad) have the potential to induce severe infections in vulnerable patient groups. Therefore, understanding Ad biology and antiviral processes is important to comprehend the signaling cascades during an infection and to initiate appropriate diagnostic and therapeutic interventions. In addition, Ad vector-based vaccines have revealed significant potential in generating robust immune protection and recombinant Ad vectors facilitate efficient gene transfer to treat genetic diseases and are used as oncolytic viruses to treat cancer. Continuous improvements in gene delivery capacity, coupled with advancements in production methods, have enabled widespread application in cancer therapy, vaccine development, and gene therapy on a large scale. This review provides a comprehensive overview of the virus biology, and several aspects of recombinant Ad vectors, as well as the development of Ad vector, are discussed. Moreover, we focus on those Ads that were used in preclinical and clinical applications including regenerative medicine, vaccine development, genome engineering, treatment of genetic diseases, and virotherapy in tumor treatment. Full article
(This article belongs to the Special Issue Research and Clinical Application of Adenovirus (AdV), 2nd Edition)
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38 pages, 2700 KiB  
Review
Evolving Horizons: Adenovirus Vectors’ Timeless Influence on Cancer, Gene Therapy and Vaccines
by Prasad D. Trivedi, Barry J. Byrne and Manuela Corti
Viruses 2023, 15(12), 2378; https://doi.org/10.3390/v15122378 - 3 Dec 2023
Cited by 10 | Viewed by 6019
Abstract
Efficient and targeted delivery of a DNA payload is vital for developing safe gene therapy. Owing to the recent success of commercial oncolytic vector and multiple COVID-19 vaccines, adenovirus vectors are back in the spotlight. Adenovirus vectors can be used in gene therapy [...] Read more.
Efficient and targeted delivery of a DNA payload is vital for developing safe gene therapy. Owing to the recent success of commercial oncolytic vector and multiple COVID-19 vaccines, adenovirus vectors are back in the spotlight. Adenovirus vectors can be used in gene therapy by altering the wild-type virus and making it replication-defective; specific viral genes can be removed and replaced with a segment that holds a therapeutic gene, and this vector can be used as delivery vehicle for tissue specific gene delivery. Modified conditionally replicative–oncolytic adenoviruses target tumors exclusively and have been studied in clinical trials extensively. This comprehensive review seeks to offer a summary of adenovirus vectors, exploring their characteristics, genetic enhancements, and diverse applications in clinical and preclinical settings. A significant emphasis is placed on their crucial role in advancing cancer therapy and the latest breakthroughs in vaccine clinical trials for various diseases. Additionally, we tackle current challenges and future avenues for optimizing adenovirus vectors, promising to open new frontiers in the fields of cell and gene therapies. Full article
(This article belongs to the Special Issue Research and Clinical Application of Adenovirus (AdV), 2nd Edition)
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Other

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9 pages, 254 KiB  
Brief Report
An Observational Study Suggests That Natural HAdV-36 Infection Decreases Blood Glucose Levels without Affecting Insulin Levels in Obese Young Subjects
by Inés Matia-Garcia, Jorge Adalberto Ocampo-Galeana, José Francisco Muñoz-Valle, José Guadalupe Soñanez-Organis, Ramón A. González, Iris Paola Guzmán-Guzmán, Linda Anahi Marino-Ortega and Isela Parra-Rojas
Viruses 2024, 16(6), 922; https://doi.org/10.3390/v16060922 - 5 Jun 2024
Viewed by 1237
Abstract
Human adenovirus-36 (HAdV-36) infection has been linked to obesity, low lipid levels, and improvements in blood glucose levels and insulin sensitivity in animal models and humans, although epidemiological studies remain controversial. Therefore, this study investigated the relationship between HAdV-36 seropositivity and glycemic control [...] Read more.
Human adenovirus-36 (HAdV-36) infection has been linked to obesity, low lipid levels, and improvements in blood glucose levels and insulin sensitivity in animal models and humans, although epidemiological studies remain controversial. Therefore, this study investigated the relationship between HAdV-36 seropositivity and glycemic control in youths. This observational study examined 460 youths (246 with normal weight and 214 obese subjects). All participants underwent assessments for anthropometry, blood pressure, circulating fasting levels of glucose, lipids, insulin, and anti-HAdV-36 antibodies; additionally, the homeostatic model assessment of insulin resistance (HOMA-IR) was calculated. In all, 57.17% of the subjects were HAdV-36 seropositive. Moreover, HAdV-36 seroprevalence was higher in obese subjects compared to their normal weight counterparts (59% vs. 55%). BMI (33.1 vs. 32.3 kg/m2, p = 0.03), and waist circumference (107 vs. 104 cm, p = 0.02), insulin levels (21 vs. 16.3 µU/mL, p = 0.003), and HOMA-IR (4.6 vs. 3.9, p = 0.02) were higher in HAdV-36-positive subjects with obesity compared to seronegative subjects. In the obese group, HAdV-36 seropositivity was associated with a reducing effect in blood glucose levels in a model adjusted for total cholesterol, triglyceride levels, age and sex (β = −10.44, p = 0.014). Furthermore, a statistically significant positive relationship was observed between HAdV-36 seropositivity and insulin levels in the obesity group. These findings suggest that natural HAdV-36 infection improves glycemic control but does not ameliorate hyperinsulinemia in obese subjects. Full article
(This article belongs to the Special Issue Research and Clinical Application of Adenovirus (AdV), 2nd Edition)
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