Viral and Host Factors in Human Respiratory Syncytial Virus Pathogenesis

NIAID, NIH, 50 South Drive, MSC 8007, Bethesda, MD 20892, USA.
Journal of Virology (Impact Factor: 4.44). 04/2008; 82(5):2040-55. DOI: 10.1128/JVI.01625-07
Source: PubMed


Human respiratory syncytial virus (RSV) was first isolated in 1956 from a laboratory chimpanzee with upper respiratory tract disease (for general reviews, see references 21, 57, 102, and 145). RSV was quickly determined to be of human origin and was shown to be the leading worldwide viral agent of serious pediatric respiratory tract disease. In a 13-year pro- spective study of infants and children in the United States, RSV was detected in 43%, 25%, 11%, and 10% of pediatric hospitalizations for bronchiolitis, pneumonia, bronchitis, and croup, respectively (110). Approximately two-thirds of infants are infected with RSV during the first year of life, and 90% have been infected one or more times by 2 years of age. The rate of hospitalization for primary infection is approximately 0.5% but can vary by situation and ethnic group and can be as high as 25% (77). RSV also is a significant cause of morbidity and mortality in the elderly, with an impact approaching that of nonpandemic influenza virus (39). RSV readily infects severely immunocom- promised individuals, most notably allogeneic bone marrow transplant recipients, causing high mortality. RSV also makes a substantial contribution to upper respiratory tract disease in individuals of all ages (59, 65). Globally, the World Health Organization estimates that RSV causes 64 million infections and 160,000 deaths annually (Initiative for Vaccine Research: respiratory syncytial virus, World Health Organization (http: //,

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    • "There is no commercial vaccine to prevent infection with HRSV (Collins & Melero 2011, Graham 2011). Important factors should be considered to explain unsuccessful attempts in the development of effective vaccine against HRSV, such as the immaturity of the immune system, the suppressor effect of the mother's antibody in the first years of life (Collins & Graham 2008, Graham 2011) and viral genetic variability (Peret et al. 1998). The most immunogenic proteins are G (adhesion) and F (fusion), which show the highest rates of amino acid variability in their outer portions (Ogra 2004). "
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    ABSTRACT: Human respiratory syncytial virus (HRSV) is an important respiratory pathogens among children between zero-five years old. Host immunity and viral genetic variability are important factors that can make vaccine production difficult. In this work, differences between biological clones of HRSV were detected in clinical samples in the absence and presence of serum collected from children in the convalescent phase of the illness and from their biological mothers. Viral clones were selected by plaque assay in the absence and presence of serum and nucleotide sequences of the G2 and F2 genes of HRSV biological clones were compared. One non-synonymous mutation was found in the F gene (Ile5Asn) in one clone of an HRSV-B sample and one non-synonymous mutation was found in the G gene (Ser291Pro) in four clones of the same HRSV-B sample. Only one of these clones was obtained after treatment with the child's serum. In addition, some synonymous mutations were determined in two clones of the HRSV-A samples. In conclusion, it is possible that minor sequences could be selected by host antibodies contributing to the HRSV evolutionary process, hampering the development of an effective vaccine, since we verify the same codon alteration in absence and presence of human sera in individual clones of BR-85 sample.
    Memórias do Instituto Oswaldo Cruz 02/2015; DOI:10.1590/0074-02760140299 · 1.59 Impact Factor
    • "Despite this high disease burden there is neither a vaccine nor an effective antiviral therapy available to date, although a humanized mAb is given to infants younger than 24 months with underlying medical problems [24]. Moreover, studies suggest that HRSV is adept at escaping host immunity [21] [24]. An HRSV vaccine that targets conserved epitopes is therefore preferred. "
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    ABSTRACT: The integration of a protein's structure with its known sequence variation provides insight on how that protein evolves, for instance in terms of (changing) function or immunogenicity. Yet collating the corresponding sequence variants into a multiple sequence alignment, calculating each position's conservation, and mapping this information back onto a relevant structure is not straightforward. We therefore built the Sequence Conservation On Protein 3D structure (scop3D) tool to perform these tasks automatically. The output consists of two modified PDB-files in which the B-values for each position are replaced by the percentage sequence conservation, or the information entropy for each position, respectively. Furthermore, text files with absolute and relative amino acid occurrences for each position are also provided, along with snapshots of the protein from six distinct directions in space. The visualization provided by scop3D can for instance be used as an aid in vaccine development or to identify antigenic hotspots, which we here demonstrate based on an analysis of the fusion proteins of human respiratory syncytial virus and mumps virus. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Proteomics 01/2015; 15(8). DOI:10.1002/pmic.201400354 · 3.81 Impact Factor
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    • "Although the identification of HRSV as an important cause of bronchiolitis in infants was made more than 55 years ago, there is still no licensed vaccine for this important respiratory pathogen (Collins & Graham, 2008). Most attempts to develop such a vaccine aim at inducing neutralizing antibodies directed against the major surface proteins, F and G (Graham, 2011). "
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    ABSTRACT: Infections with human respiratory syncytial virus (HRSV) occur globally in all age groups and can have devastating consequences in young infants. We demonstrate that a vaccine based on the extracellular domain (SHe) of the small hydrophobic (SH) protein of HRSV, reduced viral replication in challenged laboratory mice and in cotton rats. We show that this suppression of viral replication can be transferred by serum and depends on a functional IgG receptor compartment with a major contribution of FcγRI and FcγRIII. Using a conditional cell depletion method, we provide evidence that alveolar macrophages are involved in the protection by SHe-specific antibodies. HRSV-infected cells abundantly express SH on the cell surface and are likely the prime target of the humoral immune response elicited by SHe-based vaccination. Finally, natural infection of humans and experimental infection of mice or cotton rats does not induce a strong immune response against HRSV SHe. Using SHe as a vaccine antigen induces immune protection against HRSV by a mechanism that differs from the natural immune response and from other HRSV vaccination strategies explored to date. Hence, HRSV vaccine candidates that aim at inducing protective neutralizing antibodies or T-cell responses could be complemented with a SHe-based antigen to further improve immune protection.
    EMBO Molecular Medicine 10/2014; 6(11). DOI:10.15252/emmm.201404005 · 8.67 Impact Factor
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