The application of self-limiting transgenic insects in managing resistance in experimental metapopulations

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.Data sharing: raw data for this study are available as supplementary data files.1. The mass release of transgenic insects carrying female lethal self-limiting genes can reduce pest insect populations. Theoretically, substantial releases can be a novel resistance management tool, since wild type alleles conferring susceptibility to pesticides can dilute resistance alleles in target populations. A potential barrier to the deployment of this technology is the need for large-scale area wide releases. Here we address whether localized releases of transgenic insects could provide an alternative, means of population suppression and resistance management, without serious loss of efficacy. 2. We used experimental mesocosms constituting insect metapopulations to explore the evolution of resistance to the Bacillus thuringiensis toxin Cry1Ac in a high-dose/refugia landscape in the insect Plutella xylostella. We ran two selection experiments, the first compared the efficacy of ‘everywhere’ releases and negative controls to a spatially density-dependent or ‘whack-a-mole’ strategy that concentrated release of transgenic insects in sub-populations with high levels of resistance. The second experiment tested the relative efficacy of whack-a-mole and everywhere releases under spatially homogenous and heterogeneous selection pressure. 3. The whack-a-mole releases were less effective than everywhere releases in terms of slowing the evolution of resistance, which in the first experiment, largely prevented the evolution of resistance. In contrast to predictions, heterogeneous whack-a-mole releases were not more effective under heterogeneous selection pressure. Heterogeneous selection pressure did, however, reduce total insect population sizes 4. Whack-a-mole releases provided early population suppression that was indistinguishable from homogeneous everywhere releases. However, insect population densities tracked the evolution of resistance in this system, as phenotypic resistance provides access to the 90% of experimental diet containing the toxin Cry1Ac. Thus, as resistance levels diverged between treatments, carrying capacities diverged and population sizes increased under the whack- a-mole approach. Synthesis and Applications Spatially density-dependent releases of transgenic insects, particularly those targeting source populations at landscape level, could suppress pest populations in the absence of blanket area-wide management. The resistance management benefits of self-limiting transgenic insects are, however, reduced in spatially localized releases, suggesting that they are not best suited for spatially restricted ‘spot’ treatment of problematic resistance. Nevertheless, area-wide and spatially heterogeneous releases could be used to support other resistance management interventions.This work was supported by the Biotechnology and Biological Sciences Research Council [grant numbers BB/L00948X/1 to MBB and NA, and BB/L00819X/1&2 to BR]

A viral CTL escape mutation leading to immunoglobulin-like transcript 4-mediated functional inhibition of myelomonocytic cells

Viral mutational escape can reduce or abrogate recognition by the T cell receptor (TCR) of virus-specific CD8+ T cells. However, very little is known about the impact of cytotoxic T lymphocyte (CTL) epitope mutations on interactions between peptide–major histocompatibility complex (MHC) class I complexes and MHC class I receptors expressed on other cell types. Here, we analyzed a variant of the immunodominant human leukocyte antigen (HLA)-B2705–restricted HIV-1 Gag KK10 epitope (KRWIILGLNK) with an L to M amino acid substitution at position 6 (L6M), which arises as a CTL escape variant after primary infection but is sufficiently immunogenic to elicit a secondary, de novo HIV-1–specific CD8+ T cell response with an alternative TCR repertoire in chronic infection. In addition to altering recognition by HIV-1–specific CD8+ T cells, the HLA-B2705–KK10 L6M complex also exhibits substantially increased binding to the immunoglobulin-like transcript (ILT) receptor 4, an inhibitory MHC class I–specific receptor expressed on myelomonocytic cells. Binding of the B2705–KK10 L6M complex to ILT4 leads to a tolerogenic phenotype of myelomonocytic cells with lower surface expression of dendritic cell (DC) maturation markers and co-stimulatory molecules. These data suggest a link between CTL-driven mutational escape, altered recognition by innate MHC class I receptors on myelomonocytic cells, and functional impairment of DCs, and thus provide important new insight into biological consequences of viral sequence diversificatio

P09-11. Reduced replication capacity of NL4-3 chimeric viruses encoding RT-Integrase sequences from HIV-1 elite controllers

Background: Spontaneous control of HIV to 0.05). Viruses derived from HLA-B57+ EC (N = 20) appeared to replicate slower than those from B57+ progressors (N = 8) (p = 0.004). Similar results were observed between B51+ EC (N = 4) and B51+ progressors (N = 10) (p = 0.024), but not between B27+ EC (N = 9) and B27+ progressors (N = 5) (p = 0.437). Conclusion: This study extends previous observations for Gag and demonstrates that Pol variants from EC also display reduced function. The association between fitness and expression of certain HLA that present Pol epitopes suggests that immune-mediated mutations impairing viral fitness may play a key role in spontaneous control of HIV. Results indicate that HLA alleles responsible for such defects in protein function may differ among viral genes. Further identification of HLA-associated changes in HIV may allow design of vaccines targeting the most vulnerable regions of the virus