Sequence Analysis of the E3 Region and Fiber Gene of Human Adenovirus Genome Type 7h

AbstractAdenovirus type 7h is currently the predominant virulent genome type of serotype 7 isolated in Argentina, Chile, and Uruguay in association with severe infantile pneumonia. In order to characterize possible molecular determinants of pathogenicity, the nucleotide sequence of a 5904-bp fragment (76 to 93 mu) containing the entire E3 region and the fiber gene of Ad7h was established. The organization of the ORFs within the E3 region was similar to that reported for the prototype strains of Ad7 and Ad3. A comparison of the nucleotide and amino acid sequences of all ORFs revealed a higher homology between Ad7h and Ad7p than between Ad7h and Ad3 for 12.0K and 16.1K, whereas the 15.3K ORF and the adjacent fiber gene were strikingly more homologous to those of Ad3 (99.5 vs 81.1% and 98.2 vs 66.6%, respectively). The equivalent to ORF 7.7K in Ad7p was missing in Ad7h due to a deletion and a mutation affecting the start codon (ATG → ATT). Although the hemagglutinin of the Ad7h fiber could not be characterized due to its lack of activity on monkey erythrocytes, our results indicate that Ad7h is an intermediate strain 7-3

Molecular Epidemiology of Adenovirus Type 7 in the United States, 1966–20001

Genetic variation among 166 isolates of human adenovirus 7 (Ad7) obtained from 1966 to 2000 from the United States and Eastern Ontario, Canada, was determined by genome restriction analysis. Most (65%) isolates were identified as Ad7b. Two genome types previously undocumented in North America were also identified: Ad7d2 (28%), which first appeared in 1993 and was later identified throughout the Midwest and Northeast of the United States and in Canada; and Ad7h (2%), which was identified only in the U.S. Southwest in 1998 and 2000. Since 1996, Ad7d2 has been responsible for several civilian outbreaks of Ad7 disease and was the primary cause of a large outbreak of respiratory illness at a military recruit training center. The appearance of Ad7d2 and Ad7h in North America represents recent introduction of these viruses from previously geographically restricted areas and may herald a shift in predominant genome type circulating in the United States

WR1065 mitigates AZT-ddI-induced mutagenesis and inhibits viral replication

The success of nucleoside reverse transcriptase inhibitors (NRTIs) in treating HIV-1 infection and reducing mother-to-child transmission of the virus during pregnancy is accompanied by evidence that NRTIs cause long-term health risks for cancer and mitochondrial disease. Thus, agents that mitigate toxicities of the current combination drug therapies are needed. Previous work had shown that the NRTI-drug pair zidovudine (AZT)–didanosine (ddI) was highly cytotoxic and mutagenic; thus, we conducted preliminary studies to investigate the ability of the active moiety of amifostine, WR1065, to protect against the deleterious effects of this NRTI-drug pair. In TK6 cells exposed to 100 μM AZT-ddI (equimolar) for 3 days with or without 150 μM WR1065, WR1065 enhanced long-term cell survival and significantly reduced AZT-ddI-induced mutations. Follow-up studies were conducted to determine if coexposure to AZT and WR1065 abrogated the antiretroviral efficacy of AZT. In human T-cell blasts infected with HIV-1 in culture, inhibition of p24 protein production was observed in cells treated with 10 μM AZT in the absence or presence of 5–1,000 μM WR1065. Surprisingly, WR1065 alone exhibited dose-related inhibition of HIV-1 p24 protein production. WR1065 also had antiviral efficacy against three species of adenovirus and influenza A and B. Intracellular levels of unbound WR1065 were measured following in vitro/in vivo drug exposure. These pilot study results indicate that WR1065, at low intracellular levels, has cytoprotective and antimutagenic activities against the most mutagenic pair of NRTIs and has broad spectrum anti-viral effects. These findings suggest that the activities have a possible common mode of action that merits further investigation

Genomic analysis of a large set of currently—and historically—important human adenovirus pathogens

Human adenoviruses (HAdVs) are uniquely important “model organisms” as they have been used to elucidate fundamental biological processes, are recognized as complex pathogens, and are used as remedies for human health. As pathogens, HAdVs may effect asymptomatic or mild and severe symptomatic disease upon their infection of respiratory, ocular, gastrointestinal, and genitourinary systems. High-resolution genomic data have enhanced the understanding of HAdV epidemiology, with recombination recognized as an important and major pathway in the molecular evolution and genesis of emergent HAdV pathogens. To support this view and to actualize an algorithm for identifying, characterizing, and typing novel HAdVs, we determined the DNA sequence of 95 isolates from archives containing historically important pathogens and collections housing currently circulating strains to be sequenced. Of the 85 samples that were completely sequenced, 18 novel recombinants within species HAdV-B and D were identified. Two HAdV-D genomes were found to contain novel penton base and fiber genes with significant divergence from known molecular types. In this data set, we found additional isolates of HAdV-D53 and HAdV-D58, two novel genotypes recognized recently using genomics. This supports the thesis that novel HAdV genotypes are not limited to “one-time” appearances of the prototype but are of importance in HAdV epidemiology. These data underscore the significance of lateral genomic transfer in HAdV evolution and reinforce the potential public health impact of novel genotypes of HAdVs emerging in the population

Genotype Prevalence and Risk Factors for Severe Clinical Adenovirus Infection, United States 2004-2006

Recently, epidemiological and clinical data have revealed important changes with regard to clinical adenovirus infection, including alterations in antigenic presentation, geographical distribution, and virulence of the virus

Severe Infections with Human Adenovirus 7d in 2 Adults in Family, Illinois, USA, 2014

Human adenovirus 7d, a genomic variant with no reported circulation in the United States, was isolated from 2 adults with severe respiratory infections in Illinois. Molecular typing identified a close relationship with strains of the same genome type isolated from cases of respiratory disease in several provinces of China since 2009

Sidestream Smoke Exposure Increases the Susceptibility of Airway Epithelia to Adenoviral Infection

Background: Although significant epidemiological evidence indicates that cigarette smoke exposure increases the incidence and severity of viral infection, the molecular mechanisms behind the increased susceptibility of the respiratory tract to viral pathogens are unclear. Adenoviruses are non-enveloped DNA viruses and important causative agents of acute respiratory disease. The Coxsackievirus and adenovirus receptor (CAR) is the primary receptor for many adenoviruses. We hypothesized that cigarette smoke exposure increases epithelial susceptibility to adenovirus infection by increasing the abundance of apical CAR. Methodology and Findings: Cultured human airway epithelial cells (CaLu-3) were used as a model to investigate the effect of sidestream cigarette smoke (SSS), mainstream cigarette smoke (MSS), or control air exposure on the susceptibility of polarized respiratory epithelia to adenoviral infection. Using a Cultex air-liquid interface exposure system, we have discovered novel differences in epithelial susceptibility between SSS and MSS exposures. SSS exposure upregulates an eight-exon isoform of CAR and increases adenoviral entry from the apical surface whilst MSS exposure is similar to control air exposure. Additionally, the level of cellular glycogen synthase kinase 3b (GSK3b) is downregulated by SSS exposure and treatment with a specific GSK3b inhibitor recapitulates the effects of SSS exposure on CAR expression and viral infection. Conclusions: This is the first time that SSS exposure has been shown to directly enhance the susceptibility of a polarized epithelium to infection by a common respiratory viral pathogen. This work provides a novel understanding of the impact of SSS on the burden of respiratory viral infections and may lead to new strategies to alter viral infections. Moreover, since GSK3b inhibitors are under intense clinical investigation as therapeutics for a diverse range of diseases, studies such as these might provide insight to extend the use of clinically relevant therapeutics and increase the understanding of potential side effects