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Human adenoviruses (HAdV) have played a most important role in medical research, with advances in molecular biology informing recent developments in vaccinology, gene therapy, and other medical fields.recent reviews of Trends in molecular medicine We discuss the feasibility, potential dangers, and future challenges of HAdV.
prologue
HAdV only infects humans. This is a pattern common to these highly species-specific viruses. All vertebrates are susceptible to viruses containing these non-enveloped double-stranded DNA (dsDNA).
HAdV has 7 capsid proteins (3 major and 4 minor) grouped into 7 species for a total of 110. This classification is both genotypic and phenotypic. Different HAdVs infect different tissues, resulting in variability in the clinical features of infection.
HAdV has been used in medical research for about 70 years and a wealth of data is available on these small particles. This gives confidence to scientists using these viruses as vectors for various applications, such as vaccine delivery and gene therapy.
Timeline of HAdV-related knowledge
HAdV was first isolated in 1953 from tonsil and adenoid tissue of healthy humans. The following year they were found in a soldier suffering from acute respiratory illness, making them the first such agents to be isolated since the 1930s when the influenza virus came to light.
It was later discovered to have carcinogenic potential in some species. It was used to create new cell lines for biomedical research, but it also sparked a long-running vaccination campaign among US military personnel. Aimed at controlling a widespread respiratory disease, it did very well from 1996 until 1999 when it was discontinued for non-medical reasons. Military vaccination was resumed in 2011 due to repeated new outbreaks.
In 1993, it was used for CFTR gene delivery for the treatment of cystic fibrosis. This is the first valid human gene to be used. in vivo For human gene therapy. Its characterization also led to the important discovery of messenger ribonucleic acid (mRNA) splicing that won the 1993 Nobel Prize.
In 1999, deaths associated with gene therapy trials put a brake on further research in this area. The C5 strain produced the first approved oncolytic virus in 2005. About 200 trials are ongoing with adenovirus-based therapeutics and vaccines.
The first adenoviral vaccine against Ebola virus was approved for use in exceptional circumstances in 2020. Several more were developed the following year for use in the ongoing coronavirus disease 2019 (COVID-19) pandemic.
new variant
HAdV is non-seasonal and spreads rapidly within groups within closed or individual facilities such as barracks, hospitals and even day care centers. Most of these have gone unnoticed, but a few have received attention due to the severity of the disease and mortality among immunocompromised or frail individuals within the group. Some people with weak immune systems also die from these infections.
This identified several recombinants and new variants within HAdV. This introduces genetic diversity, which may facilitate transmission and virulence by introducing new functional traits.
New unique variants began to be identified, including HAdV-B14p1 in the early 2000s and B55 in 2006. The latter is a Trojan horse that incorporates a B11 neutralizing epitope and a pathogenic B14 backbone. It attracted attention because it showed an unusually high frequency of pneumonia and acute respiratory distress among apparently healthy people compared to its parent strain, B14, resulting in a higher-than-expected case fatality rate.
Similarly, the B55 variant arises from recombination of strains B11 and B14 and shows increased virulence.
Shortly thereafter, in 2013, the E4 strain was recognized to be of zoonotic interspecific origin. Recently, this strain acquired a gain-of-function mutation that adds nuclear factor 1 (NF-1), a critical replication motif required for efficient replication in human host cells that is absent in the parental E4 strain. It turned out that
This allows new variants to replicate better, enhance transmission, and explain the recent global spread of E4. Again, the E1B-19K gene deletion mutant may increase the inflammatory response to HAdV infection.
Other zoonotic HAdVs have also been reported, and some researchers suggest that repeated interspecies jumps between humans and animals may result in some recombination.
Overall, the emphasis is on exploring the potential of non-human AdV to cross species barriers and understanding its interactions with the human immune system.”
Detection of HAdV
The go-to technique for HAdV typing is the polymerase chain reaction (PCR) nucleic acid amplification test (NAAT), which also helps monitor emerging variants. However, current methods have limitations and require next-generation sequencing and whole-genome sequencing (WGS) coupled with phylogenetic analysis for epidemiological insights into outbreaks and infection control.
On the other hand, some scientists have shown that viruses can leave infected cells in both lytic and non-lytic ways after replication, which could lead to very different clinical outcomes.
clinical importance
Although considered primarily a harmless infectious agent, HAdV can cause dangerous infections in people with immature or weakened immune systems. This includes newborns and the elderly, those with chronic respiratory or heart disease, and those with weakened immune systems due to various medical conditions or taking immunosuppressive medications.
Conversely, when immunity is compromised, infections can become more serious, leading to hepatitis and pneumonia, which can ultimately be fatal in a small percentage of cases.HAdV causes epidemic keratoconjunctivitis (EKC). sometimes, most commonly due to the D8 variant. EKC is highly contagious and serious, and can take months or years to heal completely. In some cases, vision can be permanently impaired.
Eight out of ten HAdV infections occur in children under five years of age. Acute respiratory infections requiring hospitalization are commonly caused by B3 and B7 strains, particularly the latter, which replicate rapidly and cause massive release of pro-inflammatory cytokines and airway inflammation.
New HAdV outbreaks are often traced to more virulent variants resulting from animal origin (zoonosis) or recombination of human and animal adenoviruses. This could lead to more serious diseases for which the world is either ill-equipped or widely available, with no antivirals or vaccines approved for clinical use.
For example, pediatric hepatitis is thought to be due to co-infection with HAdV and adeno-associated virus (AAV), where the latter is the actual etiologic agent.
Almost everyone has been infected at least once before the sixth year of life. These infections, especially those with her HAdV A and D, are mild or asymptomatic. Such infections account for one in ten respiratory infections in children, mostly due to her HAdV types 1-7.
Viral spread includes respiratory spread via droplets or surface contamination and direct entry into the eye, causing keratoconjunctivitis. Or by fecal-oral transmission through food or water. The time to clinical manifestation is between 2 days and 2 weeks.
immune response
A robust immune response usually leads to complete resolution within a week or ten days. This includes innate humoral and cellular immunity, as well as adaptive immunity. Innate immunity triggers the release of proinflammatory cytokines and induces antiviral responses in neighboring cells, while at the same time impeding viral entry and promoting phagocytosis of virus particles. Excessive inflammation may be associated with severe pneumonia after HAdV infection.
The presence of cross-reactive T cells is important when developing AdV vectors that resist inactivation by host immune defenses. Innate immune memory, or trained immunity mediated by broadly protected memory macrophages, is suspected to prevent HAdV reinfection.
Even after clinical recovery, the virus can be shed from the intestine and respiratory tract for more than 50 days, with an even longer shedding in immunocompromised individuals. Children with HAdV pneumonia shed HAdV-B7 and -B3 for approximately 100 and 50 days, respectively.
This distinguishes HAdV from other respiratory viruses in children, such as influenza virus, which sheds for an average of 18 days, and respiratory syncytial virus, which sheds for only 4 days. It also highlights the need for longer-term implementation of infection control measures in hospitals and communities during such outbreaks.
Dormant or subclinical infections are also known, with disseminated viral disease in glandular tonsils, intestine, and other tissues, especially in immunocompromised individuals. This can influence clinical outcomes such as chronic lung disease, heart disease, and even immune responses such as graft-versus-host disease (GVHD).
process
Despite considerable toxicity, there are no specific antiviral drugs for HAdV infection, and broad-spectrum drugs are used for all their benefit. For this reason, a high-risk patient is routinely monitored for her HAdV infection after stem cell transplantation.
New therapeutic approaches include drug repurposing, the potential for T-cell therapy specific to this virus, and monoclonal antibodies.
Conclusion
HAdV may be a harmless pathogen for many, but a formidable predator for others”
It is also a valuable partner for medical scientists.
As the extent and severity of HAdV disease becomes more apparent, global collaborative surveillance will be required to detect and control outbreaks. Mechanisms of disease and transmission, consequences on host responses, and new prevention and treatment strategies are areas of research that need to be addressed.
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