Adeno-associated viruses: their impact in the human health and role in the modern healthcare

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Introduction

In July 2022, the World Health Organization (WHO) reported an outbreak of acute hepatitis of unknown aetiology affecting 35 countries worldwide. The hepatitis was severe: a significant proportion of patients required liver transplantation and approximately 2% of the children did not survive¹ [1]. The cause of the disease remains unknown to this day. The leading hypothesis regarding the etiological factor involves adeno-associated viruses (AAVs) [2–4]. At the time of the outbreak, these viruses were considered nonpathogenic, even in immunocompromised individuals [5], and were widely used as vectors for gene therapy. There are more than 4,000 patients worldwide, who have received treatment with onasemnogene abeparvovec–the first genetically engineered drug for the treatment of spinal muscular atrophy, which uses the ninth serotype of AAV (AAV9) as a vector²–including 300 in Russia³. To date, AAVs have been used as vectors for eight approved drugs⁴ [6]. The emergence of data suggesting the potential pathogenicity of AAVs has prompted renewed interest in them and a more in-depth study of their effects on the human body under conditions of natural infection.

The aim of this study was to clarify the impact of AAVs on human health based on an analysis of the available literature.

Materials and methods

The literature review was conducted by searching using the terms "аденоассоциированный вирус" and "adeno-associated virus" in the PubMed and eLIBRARY.RU databases. This query returned 16,560 articles in PubMed, of which 3,419 were published in the past 3 years; eLIBRARY.RU returned 2,363 articles, of which 520 were published in the past three years. Most of the articles focus on gene therapy, and only a few address the impact of these viruses on human health.

Results

General information. AAVs are small non-enveloped viruses whose genome consists of single-stranded DNA and contains only two genes: Rep and Cap, which encode replication and structural proteins. At the ends of the genome are inverted repeats, which play a key role in the formation of the secondary structure of the nucleic acid — the hairpin necessary for the replication and packaging of the viral genome [7].

AAVs were first discovered in 1965 as particles isolated from the kidney cells of rhesus macaques infected with simian adenovirus [8]. It was found that AAVs are capable of replicating in host cells only in the presence of helper viruses and were classified into the genus Dependoparvovirus of the family Parvoviridae because of their structural and phylogenetic similarities [9, 10]. Nucleic acid identity is 45.1% for AAVs infecting primates and increases to 72.4% when AAV types 4 and 5 are excluded as the most evolutionarily divergent serotypes [11]. Later studies demonstrated that, in addition to adenoviruses, AAVs can also replicate in the presence of helper viruses from the herpesvirus family (herpes simplex viruses types 1 and 2, varicella-zoster viruses, human herpesviruses type 6 (HHV-6), cytomegaloviruses), papillomaviruses, and bocaviruses [7]. Thus, the term "adeno-associated," which designates this type of virus, does not indicate a viral relationship and has persisted due to its historical context. Currently, 13 serotypes of the virus are known [9].

AAV is characterized by a biphasic life cycle consisting of a productive phase and a latent phase. The productive phase requires co- or superinfection with helper viruses, although some studies suggest that AAV replication is also possible when cells are exposed to physical or chemical factors [11]. In the absence of helper viruses, AAVs can enter host cells independently and persist long-term in its nucleus in an episomal form [12] or by integrating into the genome [13]. At the same time, AAVs exhibit site-specific recombination, which distinguishes them from other viruses, for which nonspecific recombination is characteristic upon integration into the genome. AAVs are detected in the host genome at the 19q13.4 chromosomal region (AAVS1), which is responsible for actin cytoskeleton assembly [14]. D. Dalwadi et al. (2021), while studying the integration frequency of the AAV vector into liver cells, found that the integration frequency is 0.7% in vivo and 1.5–2.8% ex vivo [15].

Viral co-infections lead to competition for cellular resources, and AAVs, despite their limited viral protein repertoire, possess a variety of molecular mechanisms to suppress the replication of helper viruses [7]. For example, during targeted sequencing of blood samples from patients with hepatitis non-A–E, V. Servellita et al. (2023) found that in cases of coinfection with type 2 AAV and adenoviruses, the viral load of AAVs was 12.7-fold higher than that of adenoviruses [3].

Epidemiology. AAV seroprevalence in the human population has been widely studied because of the use of AAVs as gene therapy vectors. The frequency of detection of neutralizing antibodies in the population, according to various sources, ranges from 20% to over 90%, depending on the serotype and the cohort analyzed [16–19].

Of the 13 serotypes identified to date, AAV2 is the most common [16, 17, 19, 20]. According to Q. Liu et al. (2014), it accounts for 96.6% of infections, while AAV5 accounts for 40.2% and AAV8 accounts for 82.0% [17]. Up to 82.2% of people are infected with multiple AAV serotypes simultaneously [17].

AAV infection is ubiquitous [18, 19]. However, seroprevalence rates are significantly higher in African countries: 94.6% compared to a global average of 58.5%, according to R. Klamroth et al. (2022) [18], and up to 55% versus 30–35% in other regions, according to R. Calcedo et al. (2009) [19].

Despite the widespread prevalence of AAV infection, many questions regarding its natural course in the human body remain unexplored.

Several routes of transmission have been proposed: airborne, fecal-oral, contact (sexual transmission), and vertical. The detection of AAV in cervical canal cells and semen indicates the likelihood of sexual transmission [21]. The detection of AAV DNA in cells from aborted tissue does not rule out transplacental transmission of the virus [22, 23]. AAV seropositivity in young children suggests an airborne droplet mechanism of transmission [19]. AAV target organs such as the liver, spleen, and intestines suggest that AAV transmission may occur via the gastrointestinal tract [24], a finding also supported by the detection of AAV in wastewater [29].

Clinical symptoms. AAVs exhibit broad tissue tropism, and their tissue tropism varies depending on the serotype. For example, AAV1 have the highest tropism for skeletal muscle, AAV4 and AAV5 for brain and retinal cells, AAV7 for the liver, and so on [9]. D. Huser et al. (2017) suggested in their study that the most likely sites of AAV persistence are CD3-lymphocytes. 34% (n = 83/243) of leukocyte genomic DNA samples tested positive for AAV. This hypothesis is supported by the repeated detection of the same AAV serotypes in donor lymphocytes over a 2-year period [20].

For a long time, AAVs were considered non-pathogenic, not associated with any specific disease even in immunocompromised individuals. Thus, in a study of the frequency and clinical significance of AAV viremia in recipients of hematopoietic stem cell transplants, J. Heugel et al. (2011) found that viremia was detected in only 2.8% of patients (n = 4/145) and was transient in nature. Within 7 weeks after transplantation, 2 patients died; however, AAVs were not detected in tissue samples obtained during autopsy. Consequently, the authors concluded that AAVs do not play a pathogenic role in organ-specific diseases, even in immunocompromised individuals [5].

At the same time, an increasing number of studies are emerging that demonstrate that AAVs may be responsible for the development of pathological processes in the human body [2–4, 22, 26–38].

Adeno-associated viruses and liver disease. The role of AAVs in the carcinogenesis of hepatocellular carcinoma (HCC) has been demonstrated [26–30]. T. La Bella et al. (2020), while examining liver biopsies for AAV infection, detected the presence of these viruses in 8% of tumor tissue samples, with a higher viral load in malignant tumor tissues. In 2% of patients with HCC, the authors detected recurrent somatic AAV integrations that had undergone clonal selection, localized within a limited set of oncogenes (CCNA2, CCNE1, GLI1/NHBE, TERT, etc.) [26]. Oncogenic integrations were also described in Japanese (in 1.1% of cases, n = 3/268) and Korean (in 0.7% of cases, n = 2/289) patient cohorts [27, 28]. K. Tatsuno et al. (2019), by sequencing the viralome of liver biopsy material from patients with chronic hepatitis B who developed HCC, found that AAV coinfection may increase the risk of developing HCC [29]. Although the spectrum of oncogenes involved in the integration of AAV and hepatitis B viruses is similar, AAV-associated HCC occurs much less frequently, which is likely due to the absence of prior chronic liver tissue damage [30].

Studies published in 2023 reported an association between AAV2 and severe hepatitis in children [2–4]. The first cases of hepatitis of unknown etiology were identified in Scotland, and by July 2022, the WHO had reported 1,010 probable cases in 35 countries, including 46 cases requiring liver transplantation and 22 fatalities¹ [39]. Using polymerase chain reaction (PCR) and metagenomic sequencing, three independent research groups in the UK, the US, and Scotland detected AAV2 DNA in the blood, stool, and liver tissue of hepatitis patients in 96%, 93%, and 81% of cases, respectively, compared with 9.2%, 3.5%, and 7% of cases in the control groups, respectively [2–4]. Data from epidemiological studies in the UK also provided indirect confirmation of the etiological role of AAV in the hepatitis outbreak [25, 40]. S. Gates et al. (2023) found that in 2022, the detection rate of AAV2 in pediatric respiratory samples increased sevenfold (10% vs. 1.4%) compared to samples from 2009–2013 [40]. A similar pattern was also observed by N.A. Martin et al. (2023) when studying the prevalence of AAV in wastewater samples collected at treatment plants serving up to 40% of Ireland's population [25].

The search for an answer to the question of why a virus previously considered nonpathogenic was associated with a hepatitis outbreak led to several hypotheses. Upon sequencing the AAVs isolated during the hepatitis outbreak, scientists discovered certain differences in the viruses' genomes. S. Morfopoulou et al. (2023) identified a mutation in the capsid gene of AAV2: 20 out of 21 AAV2 genomes in both the study group and the control group contained a stop codon in the gene involved in viral replication [2]. A. Ho et al. (2023) also detected mutations in the VP1-3 genes, which were more common in patients with hepatitis [4]. Interestingly, the described mutations were recorded in an AAV2 variant (AAVv66), which has a reduced ability to bind heparin, allowing it to spread more rapidly in tissues, has a more stable virion, enhanced ability to produce viral progeny, and evade neutralizing antibodies [41]. However, overall, phylogenetic analysis of Rep gene sequences from AAV2 selected during the pediatric hepatitis outbreak revealed significant genetic diversity within the isolated viruses. The strains obtained have previously been described in asymptomatic carriers [2, 40]. This observation rules out the hypothesis of the emergence of a new pathogenic AAV strain.

Another hypothesis was that co-infection led to a more severe course of the disease. According to V. Servellita (2023), 79% of children (n = 11/14) tested positive for HHV-6, and 50% (n = 7/14) for Epstein–Barr virus (EBV); in 75% of cases, children were found to be co-infected with 3–4 viruses simultaneously. However, herpesviruses were not detected in liver biopsy samples from patients. Furthermore, the viral load for EBV and HHV-6 in the patients' blood was so low (mean PCR threshold cycle values were 38.1 for EBV and 38 for HHV-6) that the detection of herpesviruses in an inactive form during the latent stage could not be ruled out [3].

A. Ho et al. (2022) found that the human leukocyte antigen (HLA) class II allele DRB1*04:01 was more common among children with hepatitis: in 93% of cases (n = 25/27) compared to 16% (n = 10/64) in the study's control group [4]. This class II HLA allele is associated with the development of type 1 autoimmune hepatitis [46] and extra-articular manifestations of rheumatoid arthritis [43], which may indicate a genetic predisposition in its carriers to higher susceptibility to AAV, leading to a severe course of the disease.

In recent years, there have been increasing reports of dose-dependent hepatitis in recipients of gene therapy products using AAV vectors, which is consistent with the hypothesis of viral hepatotropism and supports their potential role in the etiology of hepatitis outbreaks among children. D. Chand et al. (2021) investigated the effects of onasemnogene abeparvovec administration in patients with type 1 spinal muscular atrophy. It was found that 90 out of 100 patients developed hyperenzymemia (an increase in alanine aminotransferase levels to 20 times the normal range or higher) following administration of the drug [31]. In 2022, two cases of patient deaths (in Russia and Kazakhstan) from acute liver failure following administration of this drug were reported [32]. No information regarding herpesvirus infection in these patients was presented in the literature. The pathogenesis of liver damage caused by gene therapy remains unclear. Proposed mechanisms include both direct toxic effects (e.g., excessive production of vector- or transgene-derived mRNA and protein) and immune-mediated injury [44, 45]. Studies on gene therapy for hemophilia B have yielded data describing a correlation between elevated liver transaminases and reduced transgene expression, which is accompanied by an increase in anti-AAV CD8(⁺) T cells. This suggests that the elimination of transduced hepatocytes occurs as a result of the formation of a cellular immune response to the vector capsid [46, 47]. AAVs are not only hepatotropic; they can also affect other organs and systems of the human body.

The role of adeno-associated viruses in the involvement of other organs and systems. T.R. Flotte et al. (2020), D. Stone et al. (2023) describe the development of neurological complications (ataxia, paralysis, autonomic dysregulation, etc.), acute thrombocytopenia, and acute kidney injury following gene therapy using AAV vectors [44, 45]. The pathogenesis of thrombotic microangiopathy is largely associated with the activation of the humoral component of the immune response and the initiation of the classical complement pathway by anti-capsid antibodies [48]. Neurotoxicity is less likely to be immune-mediated and correlates primarily with factors affecting transduction (total dose, capsid tropism, promoter strength), as well as with the route of administration of the genetically engineered drug [45].

The influence of AAV on the reproductive system cannot be ruled out [22, 33–38]. According to a meta-analysis by Y. Guo et al. (2024), men undergoing infertility testing had a higher incidence of AAV infection (odds ratio 8.49; 95% confidence interval 2.66–27.10) compared to fertile men [33]. At the same time, according to J.R. Schlehofer et al. (2012), in a study of 146 men from couples with subfertility, the presence of AAV DNA in semen or in endocervical material from female partners was not associated with semen quality [21].

Associations between AAV infection and adverse pregnancy outcomes have been reported [22, 34–38]. E. Tobiasch et al. (1994) found that immunoglobulin M (IgM) antibodies to AAV were more frequently detected in the group of women who experienced early pregnancy loss: in 29.1% (n = 7/24) versus 9.9% (n = 6/61) in the control group [34]. In a study of abortion specimens from 81 women, C.C. Pereira et al. (2010) found that AAVs were detected more frequently in samples of decidual and chorionic tissues in spontaneous abortions: in 32.3% (n = 22/68), whereas in induced abortions–only in 7.7% (n = 1/13) [35]. T. Burguete et al. (1999) also found that when AAV is detected in amniotic fluid, the risk of preterm birth is higher (57% vs. 8%) [22]. At the same time, Z. Sayyadi-Dehno et al. (2019) found no difference in the detection of AAV in placental tissue between spontaneous and therapeutic abortions: 38.2% (n = 62/164) of the samples tested positive for AAV, of which 35 (21.6%) were from spontaneous abortions and 27 (16.6%) from induced abortions [23]. M. Matovina et al. (2004) also did not detect AAV in any of the placental tissue samples from 108 women with early spontaneous abortions [49]. K. Kiehl et al. (2002) described an association between AAV and the development of hydatidiform mole and choriocarcinoma: AAV was detected in tissue samples in 57.1% (n = 28/49) and 28.6% (n = 11/15) of cases, respectively [36]. F. Arechavaleta-Velasco et al. (2006) suggested that AAV infection inhibits trophoblast invasion, leading to preeclampsia: AAV was detected in trophoblast cells in women who developed preeclampsia in 55.0% (n = 22/40) of cases, compared with 18.5% (n = 5/27) in the control group [37]. Two years later, American scientists confirmed the impact of primary AAV infection and reactivation on adverse reproductive outcomes based on serological studies: when maternal IgM to AAV was detected in early pregnancy, the risk of preeclampsia and stillbirth was 5.6 times higher, and the risk of preterm birth was 7.6 times higher [38].

Despite data on the potential pathogenicity of AAV, there are studies demonstrating the positive effects of AAV on human health.

The positive impact of adeno-associated viruses on human health. To date, a considerable body of evidence has accumulated accumulated showing that AAVs prevent the development of cervical cancer by suppressing HPV-induced cellular transformation [50–52]. This mechanism is likely due to the fact that, upon superinfection, AAVs begin to actively replicate, causing the death of cells infected with pathogenic viruses [14]. This hypothesis is supported by the findings of H. Mayor et al. (1976), who demonstrated that antibodies to AAVs are detected in only 14% of patients with cervical cancer compared to 85% of healthy women [50]. Later, B. Georg-Fries et al. (1984) found that antibody titers against AAV were lower in the sera of patients with cervical cancer compared to a control group of patients of the same age [51]. Furthermore, L. Freitas et al. (2012) in women co-infected with HPV and AAV compared to those infected with HPV alone [52]. At the same time, there are studies in which no effect of AAV on cervical carcinogenesis was detected [53]. For example, a 2017 Iranian study found a low prevalence of AAVs in cervical biopsy specimens and no correlation between cervical cancer and AVV-infection (14.8% of cervical cancer cases and 14% of control cases) [54].

When discussing AAVs, it is impossible not to mention them as the leading platform in gene therapy.

Adeno-associated viruses in gene therapy. The first clinical trial of an AAV vector in humans was approved in 1995 [44]. In 2012, the European Medicines Agency (EMA) approved the first AAV-vector-based gene therapy drug, alipogen tiparvovec, for the treatment of lipoprotein lipase deficiency [55].

The lack of data on AAV pathogenicity, the ability of recombinant vectors to transduce both quiescent and dividing cells, and the capacity for long-term transgene expression, as well as low immunogenicity and broad tissue tropism of different serotypes are properties that have led to the widespread use of AAV in genetic engineering [6].

To date, the number of AAV-based gene therapy products approved for clinical use has grown significantly: these include treatments for retinitis pigmentosa, spinal muscular atrophy, hemophilia types A and B, and aromatic amino acid decarboxylase deficiency [55]. In November 2025, the eighth AAV-vector-based drug–onasemnogene abeparvovec–was approved for the treatment of spinal muscular atrophy via intrathecal administration for patients over 2 years of age⁴.

According to L. Suarez-Amaran et al. (2025), as of January 27, 2025, there were 343 clinical trials of gene therapy products based on the AAV vector [56]. An additional search on clinicaltrials.gov reveals that the number of trials had increased to 371 by November 25, 2025.

Initially, the clinical application of AAV vectors was focused primarily on the treatment of monogenic diseases, but to date, their use has expanded significantly and covers a wide range of pathologies: from neurodegenerative and ophthalmological to metabolic, immune, and infectious. Thus, the literature describes developments in the use of AAV vectors in the treatment of stroke [57], familial hypercholesterolemia [58], ulcerative colitis [59], and Alagille syndrome [60]. A promising method for the prevention and treatment of HIV infection is the delivery of monoclonal antibodies against HIV using AAV vectors [61]. There is progress in the development of a contrast agent for use in magnetic resonance imaging of the brain to enhance the caudate nucleus using the chemical exchange saturation transfer (CEST) method [62]. Clinical trials are underway for the treatment of approximately 80 diseases, including hemophilia types A and B, spinal muscular atrophy, retinitis pigmentosa, wet age-related macular degeneration, Parkinson's disease, and Leber's congenital amaurosis [56].

Discussion

The effects of AAVs on the human body are ambiguous. There is evidence of both neutral interactions and pathogenic effects, as well as a protective role for these viruses.

AAV attracted the attention of the medical community in 2022, during an outbreak of hepatitis of unknown etiology, when independent studies began to emerge proposing the hypothesis that AAV was the likely etiological factor [2–4].

Several hypotheses were investigated to determine the cause of the hepatitis outbreak Toxic causes of hepatitis were ruled out, as was the development of drug-induced liver injury due to high doses of paracetamol [63]. According to data from the UK Health Agency, three-quarters of patients received paracetamol, but no cases of intake at doses exceeding therapeutic levels were recorded⁵. Nevertheless, the lack of data on serum levels of paracetamol and its adducts — products of its covalent binding to proteins — limits the ability to definitively assess its role in the development of the disease. The potential role of SARS-CoV-2 infection, including post-infectious immune mechanisms leading to the development of multisystem inflammatory syndrome in children, was also examined [64]. However, the detection rate of SARS-CoV-2 in patients was low and did not exceed that of the general population (52.2% vs. 59.0–72.4%) [4], which does not allow for a direct causal relationship to be established. Initially, group F adenoviruses (type 41) were considered the most likely etiological agent. The lack of differences in the severity of outcomes between patients with positive and negative test results cast doubt on its leading role [65] and subsequently led to the emergence of the hypothesis regarding AAV.

This outbreak raised questions about why infection with viruses previously considered nonpathogenic [5] led to such a severe course of the disease. The possibility of a new AAV strain emerged, but it has not been confirmed. The strains isolated had previously been described in asymptomatic carriers [2, 40]. This observation rules out the hypothesis of a new pathogenic AAV strain. The widespread circulation of AAV may have been linked to the emergence of a large segment of the population living in isolation due to the COVID-19 pandemic. The wearing of masks and social distancing, aimed at limiting the transmission of SARS-CoV-2, have been associated with a decrease in the incidence or cessation of circulation in the community of a number of infectious agents [62, 66, 67]. As a result, the proportion of the population susceptible to these diseases has increased, especially among children aged 1 to 3 years. Reports on the genetic predisposition of children who have had hepatitis are also significant: 93% were found to carry the human leukocyte antigen (HLA) class II allele DRB1*04:01, compared with 16% in the control group [4]. Once restrictions were lifted, genetically susceptible children may have been at higher risk of initial exposure to both adenoviruses and AAV, which could have contributed to the emergence of a wave of severe disease. Thus, the potential of AAV2 to cause severe disease may have been associated with specific circumstances, such as the host's genetic background and increased post-pandemic susceptibility. At the same time, it cannot be ruled out that cases of AAV-associated diseases occurred earlier but remained etiologically unverified due to the lack of routine AAV testing.

The role of AAVs in the development of other pathologies, particularly those of the reproductive system, has also been described. AAVs may be associated with both infertility and reproductive losses: spontaneous abortion, preterm birth, stillbirth, and preeclampsia [22, 33–38]. An increasing body of data describes the role of AAVs in the carcinogenesis of HCC [26–30], the development of hepatitis [2–4], including as a result of gene therapy [31, 32, 44, 45].

At the same time, the benefits of AAVs in healthcare should not be underestimated. These viruses are widely used in clinical trials of gene therapy products as vectors for the treatment of a wide range of severe and life-threatening diseases: retinitis pigmentosa, spinal muscular atrophy, hemophilia types A and B, and aromatic amino acid decarboxylase deficiency. Development of drugs for the treatment of other conditions is actively underway, expanding the range of applications for AAV vectors [6, 56]. Furthermore, a positive effect of AAV has been described: the prevention of cervical cancer development by suppressing HPV replication [50–52, 54]. Thus, AAVs may also have an independent protective effect on human health, in addition to the enormous contribution these microorganisms make to saving countless human lives through the use of vector-based drugs. Despite the available data regarding the risk of hepatitis development associated with the use of AAV vectors, this risk does not currently outweigh the undoubted benefits of the therapy.

Conclusion

Accumulating evidence suggests that the role of AAVs in the development of human diseases may be underestimated. One reason for this underestimation is the absence of AAV testing in patient screening protocols, as well as the lack of laboratory diagnostic tests for AAVs in routine clinical practice.It is possible that AAVs play a certain role in the atypically severe course of infectious diseases, acting as an undiagnosed co-factor, and could contribute to the etiological elucidation infectious diseases of unknown origin. To date, this issue has not been sufficiently studied. Despite the widespread prevalence of AAV according to seroepidemiological studies, there are no precise data regarding the natural course of AAV infection in the human body. The authors of many studies agree that the liver is the primary organ affected by AAV. There is evidence regarding the role of AAV in the carcinogenesis of hepatocellular carcinoma and the hepatotoxicity of AAV-based vectors. Patients with the HLA class II variant DRB1*04:01 require particular vigilance regarding the possibility of developing overt AAV infection. Further research is warranted. Such studies would be particularly significant for patients receiving AAV-vector gene therapy. As the number of AAV-vector-based gene therapy products and the number of patients receiving them increase, the number of AAV-associated adverse events is expected to rise as well. A striking example of this is the occurrence of patient deaths due to the development of liver failure following administration of these products. Undoubtedly, the positive effects of these drugs far outweigh the potential risks of adverse events and do not diminish their benefits; however, the available data indicate the need for caution regarding the possibility of AAV-associated adverse events.

The potential role of AAV in reproductive loss also warrants close attention.

Given the potential risk of liver damage, it is advisable to screen prospective recipients of AAV-vector-based gene-engineered drugs for active viral infections, the pathogens of which may simultaneously act as helper viruses for AAV and possess hepatotropic activity.

Thus, scientific research into the etiological role of AAV in the development of various pathologies and the characteristics of the human body that determine susceptibility to this pathogen is of great interest to public health practice. AAV warrants greater scientific attention. It is evident that, at present, "technology is outpacing knowledge," outstripping our understanding of the mechanisms of life processes in macro- and microorganisms, as well as interspecies interactions. The development of test systems aimed at detecting AAVs is of extreme relevance. The ability to widely diagnose AAVs will allow for a deeper understanding of their role in the development of various pathologies or confirm the absence thereof.

¹ World Health Organization (12 July 2022). Disease Outbreak News; Acute hepatitis of unknown etiology in children – Multi-country. Available at: https://www.who.int/emergencies/disease-outbreak-news/item/2022-DON400 (access date: 22.12.2025).

² Novartis Pharmaceuticals Corporation. Zolgemsma is the only one-time gene replacement therapy for SMA. Available at: https://www.zolgensma-hcp.com/about-zolgensma/about-zolgensma (access date: 14.12.2025).

³ Saving children with SMA: The Foundation "Krug Dobra" acquires unique drugs. Available at: https://фондкругдобра.рф/спасение-детей-со-сма-фонд-круг-добра (access date 16.11.2025).

⁴ FDA Approves Gene Therapy for Treatment of Spinal Muscular Atrophy (24 November 2025). Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-gene-therapy-treatment-spinal-muscular-atrophy?utm_source=chatgpt.com (access date: 02.01.2026).

⁵ UKHSA. Investigation into acute hepatitis of unknown aetiology in children in England. Technical briefing 2. May 6, 2022. Available at: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1073704/acute-hepatitis-technical-briefing-2.pdf (access date: 14.12.2025).

About the authors

Ekaterina A. Ulanova

Federal Research and Clinical Center for Infectious Diseases

Author for correspondence.
Email: chuhnina_ekaterina@mail.ru
ORCID iD: 0009-0003-1143-7339

Junior Research Fellow of Research Department of Viral Hepatitis and Liver Diseases

Russian Federation, 197022, Saint Petersburg

Vera A. Greshnyakova

Federal Research and Clinical Center for Infectious Diseases; St. Petersburg State Pediatric Medical University; St. Petersburg State University

Email: veramamayeva@gmail.com
ORCID iD: 0000-0002-4509-5352
SPIN-code: 9914-9205

PhD, Head of the Research Department of Viral Hepatitis and Liver Diseases; Associate Professor of the Department of Infectious Diseases in Children of Faculty of Postgraduate and Additional Professional Education; Associate Professor of the Department of Infectious Diseases

Russian Federation, 197022, Saint Petersburg; 194100, Saint Petersburg; 199034, Saint Petersburg

References

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