Browsing by Author "Wood, Natasha"

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    Experimental evidence indicating that mastreviruses probably did not co-diverge with their hosts
    (BioMed Central Ltd, 2009) Harkins, Gordon; Delport, Wayne; Duffy, Siobain; Wood, Natasha; Monjane, Aderito; Owor, Betty; Donaldson, Lara; Saumtally, Salem; Triton, Guy; Briddon, Rob; Shepherd, Dionne; Rybicki, Edward; Martin, Darren; Varsani, Arvind
    BACKGROUND:Despite the demonstration that geminiviruses, like many other single stranded DNA viruses, are evolving at rates similar to those of RNA viruses, a recent study has suggested that grass-infecting species in the genus Mastrevirus may have co-diverged with their hosts over millions of years. This "co-divergence hypothesis" requires that long-term mastrevirus substitution rates be at least 100,000-fold lower than their basal mutation rates and 10,000-fold lower than their observable short-term substitution rates. The credibility of this hypothesis, therefore, hinges on the testable claim that negative selection during mastrevirus evolution is so potent that it effectively purges 99.999% of all mutations that occur. RESULTS: We have conducted long-term evolution experiments lasting between 6 and 32 years, where we have determined substitution rates of between 2 and 3 x 10-4 substitutions/site/year for the mastreviruses Maize streak virus (MSV) and Sugarcane streak Reunion virus (SSRV). We further show that mutation biases are similar for different geminivirus genera, suggesting that mutational processes that drive high basal mutation rates are conserved across the family. Rather than displaying signs of extremely severe negative selection as implied by the co-divergence hypothesis, our evolution experiments indicate that MSV and SSRV are predominantly evolving under neutral genetic drift. CONCLUSION: The absence of strong negative selection signals within our evolution experiments and the uniformly high geminivirus substitution rates that we and others have reported suggest that mastreviruses cannot have co-diverged with their hosts.
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    HIV evolution in early infection: selection pressures, patterns of insertion and deletion, and the impact of APOBEC
    (Public Library of Science, 2009) Wood, Natasha; Bhattacharya, Tanmoy; Keele, Brandon F; Giorgi, Elena; Liu, Michael; Gaschen, Brian; Daniels, Marcus; Ferrari, Guido; Haynes, Barton F; McMichael, Andrew
    Author Summary HIV is a rapidly evolving virus, displaying enormous genetic diversity between and even within infected individuals, with implications for vaccine design and drug treatment. Yet, recent research has shown that most new infections result from transmission of a single virus resulting in a homogeneous viral population in early infection. The process of diversification from the transmitted virus provides information about the selection pressures experienced by the virus during the establishment of a new infection. In this paper, we studied early diversification of the envelope gene in a cohort of 81 subjects acutely infected with HIV-1 subtype B and found evidence of adaptive evolution, with a proportion of sites that tended to diversify more rapidly than expected under a model of neutral evolution. Several of these rapidly diversifying sites facilitate escape from early cytotoxic immune responses. Interestingly, hypermutation of the virus, brought about by host proteins as a strategy to restrict infection, appeared to be associated with early immune escape. In addition to single base substitutions, insertions and deletions are an important aspect of HIV evolution. We show that insertion and deletion mutations occur evenly across the gene, but are preferentially fixed in the variable loop regions.
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    Refining the HIV-1 glycan shield model: dynamics of a heterogeneous envelope trimer and empirical prediction of glycan processing
    (2019) Garrard, Clare; Wood, Natasha; Anthony, Colin
    The HIV-1 surface protein, Envelope (Env), is covered in asparagine-linked glycans, which interact with the human immune system and are thus important as potential vaccine targets. Laboratory studies have shown that the glycan type and form can differ substantially at each glycan site on Env clones. However, these studies are limited by time and cost and rely on biosynthetic assumptions to elucidate the structure of branched glycans. Furthermore, glycan heterogeneity creates challenges when determining the three-dimensional structure of Env, which has resulted in the use of methods that restrict glycan processing to produce uniform glycans for these studies. Computational methods are used to complement the laboratory studies; however, due to the limitations of modelling software, even computational studies have focussed on uniformly glycosylated Env models using a limited set of high-mannose glycans, rather than a mix of glycan types. To bridge this gap, this study set out to examine the structural differences of two computationally glycosylated HIV-1 Env trimers, one uniformly glycosylated, and the other based on the heterogeneous glycosylation of a laboratory determined gp160 strain. A secondary aim was to estimate whether the type of glycan is predictable using computational techniques, since these are less expensive and time consuming than laboratory studies. Using 500 ns molecular dynamics (MD) simulations, it was found that the heterogeneously glycosylated trimer had 64% greater stability, likely due to the presence of 25% more hydrogen bonds, as well as stabilising bonds which appeared to prevent asymmetrical movements. Furthermore, by focussing on the heterogeneously glycosylated trimer, a computational method based on surface area was explored to estimate the accessibility to enzymes involved in glycan processing, and to use this measure as a predictor of the glycan type. The results of this study highlight the differences between a uniformly, and a heterogeneously, glycosylated trimer, and suggest that previous MD studies, which used uniformly glycosylated trimers, may not sufficiently describe the structural dynamics of HIV-1 Env. Notably, complex glycans appear to stabilise the trimer to a greater extent than the high-mannose glycans used in previous studies. Thus, it is evident that research on Env models should incorporate a more diverse set of glycans in order to deepen our understanding of the dynamics of Env, which will, in turn, further our understanding of its interactions with antibodies and anti-HIV compounds.