Extent of Tumor Evolution as Assessed by Numbers of Nonsynonymous Somatic Mutations Correlates with the Effectiveness of Anti-Checkpoint Therapy

It would be hard to identify an approach to cancer treatment that has received more attention recently than anti-checkpoint therapy (Pollack, 2015).  This strategy for eliminating tumor cells is based on interfering with one or another pathway that inhibits the initial activation or functions of T cells, such as CD8+ cytotoxic T cells (CTL).  Activated tumor-specific CTL can directly kill their targets.  However, if copies of the T-cell surface molecule, PD-1, are bound by their physiological ligands on tumor cells, either PD-L1 or PD-L2, or other cells the ability of the T cell to perform its functions is substantially reduced.  A report published in Science (2015) by Rizvi et al. last month addresses the question of whether tumor mutation burden correlates with response to anti-checkpoint therapy for non-small cell lung cancer (NSCLC).

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Putting the Kill in “Shock and Kill”: Overcoming Evolutionary Obstacles to HIV Cure

According to estimates by the World Health Organization, in 2013 on the order of 35 million people were infected with HIV worldwide (http://www.who.int/gho/hiv/en/).  Globally, about 1.5 million people are believed to have died from AIDS-related diseases in that year.  Substantial, although perhaps not insurmountable, obstacles to the development of a highly effective vaccine for HIV-1 have increased interest in curative strategies.  A key challenge to cure strategies is that infected people harbor a latent reservoir of infected CD4+ memory T cells that do not express significant amounts of viral proteins.  The paucity of viral proteins in these cells makes it more difficult to identify infected cells and eradicate them.  A new study (Deng et al., 2015) in Nature from Robert Siliciano’s lab at Johns Hopkins identifies an additional difficulty faced by one of the currently popular approaches to curative therapy but also, more optimistically, suggests a way to overcome this challenge. (more…)

Cellular ‘Gold’: Competition for Iron as the Cause of Reciprocal Positive Selection of Host and Pathogen Iron-Binding Proteins

Iron is a critical metal for essential cellular processes, such as respiration, in both human and microbial cells.  Thus, in the context of infection, iron is a high-value cellular commodity and an evolutionist might reasonably expect a metallic tug-of-war between host and pathogen iron-binding proteins or other iron-binding molecules (siderophores).  This speculation is impressively supported in a paper published this month (Barber and Elde, 2014).  These authors provide strong evidence for positive selection affecting several sites in host (transferrin, Tf) and pathogen (transferrin binding protein A) iron-binding proteins based on a combination of genetic, structural, and functional experimental methods. (more…)

Epistasis in Adaptive versus Stochastic Evolution of the Influenza A Virus Nucleoprotein Gene

Epistasis refers to the influence of one genomic mutation or variant on the phenotypic effects of another mutation or variant.  Based on available evidence and theory, this phenomenon has a major influence on evolutionary trajectories for organisms of all sorts.  The role of epistasis has been studied primarily in the context of adaptive evolutionary change.  In a recent paper (2014), Gong and Bloom attempt to determine the relative frequencies of epistatic interactions in adaptive versus stochastic evolution, i.e. evolution driven by selection as opposed to evolution resulting from random processes without a significant selective ‘pressure.’  Gong and Bloom perform this comparison by analyzing homologous nucleoprotein (NP) genes in human and swine influenza A viruses.  The authors argue that the human viruses are subject to substantially more intense selection than the swine viruses since domestic swine are much shorter lived and their viruses are not as likely to be subjected to immune memory responses. (more…)