What is the role of adenoviruses in human health?

With advances in molecular biology informing recent developments in vaccinology, gene therapy and other areas of medicine, human adenoviruses (HAdV) are of paramount importance in medical research. A recent review in Trends in Molecular Medicine examines the promise of HAdV, their potential dangers and future challenges.

Study: Adenoviruses in medicine: harmless pathogen, predator or partner. Image credit: Christoph Burgstedt/Shutterstock

Introduction

HAdVs infect only humans, a pattern common to these highly species-specific viruses. All vertebrates are susceptible to these viruses containing non-enveloped double-stranded DNA (dsDNA).

HAdVs have seven capsid proteins, three major and four minor, and are grouped into seven species, totaling 110. This classification is both genotypic and phenotypic. Different HAdVs infect different tissues, leading to variations in the clinical features of the infection.

HAdVs have been used for medical research for approximately 70 years, and there is much data available on these small particles. This gives confidence to scientists who use these viruses as vectors for various applications, including vaccine delivery or gene therapy.

Timeline of knowledge related to HAdV

HAdVs were first isolated in 1953 from tonsil and adenoid tissue of healthy humans. The following year, they were found in military personnel suffering from acute respiratory illness, the first such pathogen to be isolated since the 1930s, when the influenza virus first emerged.

It was then discovered to have oncogenic potential in some species. It was used to create a new cell line for biomedical research, but it also sparked a long immunization campaign for US military personnel. Intended to control widespread respiratory disease, it worked remarkably well until 1996-1999, when it was discontinued for non-medical reasons. Repeated new outbreaks led to the restart of military vaccination in 2011.

In 1993, it began to be used for therapeutic delivery of the CFTR gene in cystic fibrosis, the first effective human gene to be used in vivo for human gene therapy. Its characterization also led to the landmark discovery of messenger ribonucleic acid (mRNA) splicing, which won the 1993 Nobel Prize.

In 1999, a death related to a gene therapy trial occurred, halting further research in the field. Strain C5 gave rise to the first approved oncolytic virus in 2005. Currently, almost 200 trials of adenovirus-based therapies and vaccines are underway.

In 2020, the first adenovirus vaccine was approved against the Ebola virus for use in exceptional circumstances. In the following year, several more were developed for use in the ongoing coronavirus disease 2019 (COVID-19) pandemic.

Emerging variants

HAdV is not seasonal and spreads rapidly in clusters in closed or isolated facilities, including barracks, hospitals or even day care centers. Most of these go unnoticed, but a few have attracted attention due to the severity of the disease and some deaths among immunocompromised or weak individuals in the group. Some people with no known disease and normal immune systems have also died from these infections, although rarely.

This led to the identification of some recombinants and new variants among HAdV. This introduces genetic diversity that may favor transmission or virulence by introducing new functional traits.

New endemic variants began to be identified, including HAdV-B14p1 in the early 2000s and B55 in 2006. The latter is a Trojan horse containing a B11-neutralizing epitope and a pathogenic B14 backbone. It attracted attention because of the unusually high incidence of pneumonia and acute respiratory distress among people in apparently good health, with higher than expected mortality rates as a result compared to the parent B14 strain.

Similarly, the B55 variant arose from the recombination of strains B11 and B14 and showed increased pathogenicity.

Soon after, in 2013, the E4 strain was recognized to be of zoonotic cross-species origin. This strain was recently found to have acquired gain-of-function mutations adding a key replication motif, nuclear factor 1 (NF-1), absent in the E4 parental strain but required for efficient replication in human host cells.

This allows the new variant to reproduce better and improve transmission, explaining the recent global spread of E4. Again, the E1B-19K gene deletion mutant can increase the inflammatory response to HAdV infection.

Other zoonotic HAdVs have also been reported, and some researchers suggest that repeated interspecies jumps between human and animal occur with several recombinations.

In general, increasing emphasis has been placed on exploring the potential of non-human AdVs to cross species barriers and understanding their interactions with the human immune system.”

HAdV detection

The main technology for HAdV typing is the polymerase chain reaction (PCR) nucleic acid amplification test (NAAT), which also helps monitor emerging variants. However, current methods have their limitations, calling for next-generation sequencing and whole-genome sequencing (WGS) combined with phylogenetic analysis for epidemiological insights into outbreaks and infection control.

Meanwhile, some scientists have shown that the virus can leave infected cells after replication by both lytic and non-lytic methods, which can lead to quite different clinical outcomes.

Clinical significance

HAdVs are largely considered harmless infectious agents, but can cause dangerous infections in people with immature or weakened immunity. This may include newborns or very old people suffering from chronic respiratory or heart diseases and those with weakened immunity due to various diseases or taking immunosuppressive drugs.

Conversely, in a weakened immune system, the infection can become serious, causing hepatitis or pneumonia, which can ultimately be fatal in a minority of cases. HAdV can also cause epidemic keratoconjunctivitis (EKC), most commonly due to the D8 variant. EKC is highly infectious and severe and may take months or years to clear up completely. In some cases, vision can be permanently damaged.

Eight out of ten HAdV infections occur before the age of five. Acute respiratory infections requiring hospitalization are usually due to B3 and B7 strains, especially the latter, which replicates more rapidly and causes greater release of inflammatory cytokines and airway inflammation.

New outbreaks of HAdV have been traced to variants with greater virulence, often arising from animal sources (zoonotic infections) or recombination of human and animal adenoviruses. This could lead to more severe diseases for which the world is ill-equipped without antivirals or vaccines approved for clinical use or widely available.

For example, pediatric hepatitis is suspected to be due to the coinfection of HAdV and adeno-associated virus (AAV), the latter being the actual pathogenic agent in this case.

Almost all people are infected at least once by the time they reach their sixth year of life. These infections, especially with HAdV A and D, are mild or asymptomatic. Such infections account for one-tenth of childhood respiratory infections, mainly due to HAdV types 1-7.

Spread of the virus is respiratory, through droplets or surface contamination, including directly into the eye to cause keratoconjunctivitis; or by feco-oral transmission, including through food and water. Time to clinical illness varies from two days to two weeks.

The immune response

A strong immune response usually results in complete healing within a week or ten days. This includes innate humoral and cellular immunity as well as adaptive immunity. Innate immunity causes the release of inflammatory cytokines, triggering antiviral responses in neighboring cells, while preventing virus entry and enhancing phagocytosis of viral particles. Excessive inflammation may be associated with severe pneumonia after HAdV infection.

The presence of cross-reactive T cells is important in the development of AdV vectors that will resist inactivation by host immune defenses. Memory of innate immunity or learned immunity mediated by broadly protective memory macrophages has been suggested to prevent HAdV re-infection.

Even after clinical recovery, virus can be shed from the gut and respiratory tract for more than 50 days, with immunocompromised people showing even longer shedding. Children with HAdV pneumonia shed HAdV-B7 and -B3 for ~100 and ~50 days, respectively.

This distinguishes HAdV from other respiratory viruses in children, such as influenza virus, which is shed for an average of 18 days, and respiratory syncytial virus for only four days. It also highlights the need for more sustained implementation of infection control measures in hospitals and the community during such outbreaks.

Passive or subclinical infection is also known, especially in immunocompromised individuals, with disseminated viral disease in the adenotonsillar tissues, intestines, and other tissues. This can affect clinical outcomes such as chronic lung disease, heart disease, or even immunological responses such as graft-versus-host disease (GVHD).

Treatment

Despite their considerable toxicity, there are no specific antiviral agents for HAdV infection, and broad-spectrum drugs are used for whatever benefit they offer. For this reason, high-risk patients are routinely monitored for HAdV infection after stem cell transplantation.

New therapeutic approaches include drug retargeting, the potential of T-cell therapy specific to this virus, and monoclonal antibodies.

Conclusion

While HAdV may be a harmless pathogen to many, to some it can become a fearsome predator.”

It is also a valuable partner for medical scientists.

As the scope and severity of HAdV disease become more apparent, global collaborative surveillance is needed to detect and control outbreaks. The mechanism of disease and transmission, outcomes in terms of host response, and new strategies for prevention and treatment are areas of research that need to be addressed.

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