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Viral pathogens

RNA viruses are incapable of correcting the frequent mistakes that occur during viral replication. The net result is the generation of an enormous amount of genetic diversity within a population of replicating RNA viruses. This genetic flexibility can allow RNA viruses to alter their antigens and thus overcome challenges posed by the immune system or drug therapy interventions, provided the targeted residues can tolerate escape-enabling change.

We try to explore the impact of immune selection on viral diversity both on the scale of an individual infection and within the host population at large, primarily with respect to three viral pathogens: dengue, influenza and HIV. This work comprises a set of studies highlighting the roles of structural constraints on critical antigenic determinants, interactions between immune responses to different antigenic types, host lifespan, and the degree of mixing between different host populations in determining the epidemiology and within-host dynamics of these pathogen systems.

Dengue. Dengue exists in humans as a collection of four antigenically related, co-circulating serotypes. Protection from one, however, is believed to be a risk factor for severe disease manifestations upon secondary, heterologous infection. Assuming that such clinical severity at second infection is linked to enhanced transmission and/or susceptibility to infection can generate the complex and persistent cyclical or chaotic epidemic behaviour that seems typical of dengue (1, 2). The importance of third and fourth infections in dengue epidemiology is unclear, but we have suggested that they may have significant consequences for estimations of dengue’s overall transmission potential (3). We have also shown that ecological factors may also be of critical importance in dengue’s recent molecular evolution and epidemiology (4). We therefore expect that integrating both immunological and ecological factors into mathematical models of dengue will yield invaluable insights into the contemporary epidemiology of dengue.

Influenza. By contrast with dengue, human influenza viruses are known to be in rapid antigenic flux, manifesting in the sequential replacement of antigenic types. This behaviour is often attributed to the action of “antigenic drift” but this is hard to justify (5). We (and others) have consequently proposed alternatives, with ours solving the riddle of apparent drift through the action of immune selection acting on an ultimately restricted antigenic space (6). We are currently trying to establish the biological correlates of this model and investigate its application to the differing patterns of influenza evolution apparent in other host species such as pigs and birds.

HIV. Recently we have also been trying to understand the within-host evolution of HIV-1, in particular why control of the virus eventually breaks down in the majority of infected individuals.

References

  1. Ferguson, N., Anderson, R. & Gupta, S. (1999) The effect of antibody-dependent enhancement on the transmission dynamics and persistence of multiple-strain pathogens. Proc Natl Acad Sci U S A 96, 790. PDF
  2. Recker M, Blyuss KB, Simmons CP, Hien TT, Wills B, Farrar J, & Gupta S (2009). Immunological serotype interactions and their effect on the epidemiological pattern of dengue. Proc Biol Sci, 276(1667):2541-8. PDF
  3. Wikramaratna, P.S., Simmons, C.P., Gupta, S., Recker, M. (2010). The effects of tertiary and quaternary infections on the epidemiology of dengue. PLoS One. 5:e12347. PDF
  4. Lourenço J, & Recker M (2010). Viral and epidemiological determinants of the invasion dynamics of novel dengue genotypes. PLoS Negl Trop Dis, 4(11):e894. PDF
  5. Wikramaratna, P.S., Gupta S. (2009). Influenza outbreaks. Journal of Cellular Microbiology. 11:1016-24. PDF
  6. Recker M, Pybus OG, Nee S, & Gupta S (2007). The generation of influenza outbreaks by a network of host immune responses against a limited set of antigenic types. Proc Natl Acad Sci U S A, 104(18):7711-6. PDF