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Genetically Diverse Viral Antigens Needed to Win the Fight Against Viral Pathogens

AUG 21, 2016 | WILLIAM PERLMAN, PHD, CMPP
A new model of the within-host evolutionary arms race between viral pathogens and the adaptive immune responses intended to fight them suggests that vaccines based on genetically diverse sets of viral antigens may be more likely to stimulate the production of antibodies capable of neutralizing broad panels of virions, according to the results of a study published recently in PLoS Genetics1.
 
The study was presented by Armita Nourmohammad, PhD, an associate research scholar from the Joseph-Henri Laboratories of Physics and Lewis-Sigler Institute for Integrative Genomics at Princeton University, in collaboration with Jakub Otwinowski, PhD, and Prof. Joshua Plotkin, PhD, from the biology department at the University of Pennsylvania. The study was motivated by a need to elucidate the "generic features and relevant parameters" of the evolutionary arms race that would allow for the development of the aforementioned broadly neutralizing antibodies, and their early development in particular. Previous studies attempted to address this problem with detailed mechanistic modeling of germinal centers in response to a few viral types, and make many assumptions regarding the details of affinity maturation2,3. Other phenomenological models, which took into account the genetic diversity amongst the infecting viruses, relied primarily on numerical simulations4,5. In this study, the analytical description for the phenomenological model of immune-viral co-evolution allowed the authors to identify a small number of key parameters to describe the co-evolutionary dynamics and turnover in the diverse populations of antibodies and viruses.
 
To further investigate the mechanisms underlying the co-evolution of antibodies and viruses, Dr. Nourmohammad and her colleagues developed and employed a phenomenological model for the evolution of the distribution of binding affinities between viral and receptor populations based on the effects of mutations, selection, and reproductive stochasticity. Subsequent to the development of the model and assessment of its parameters, the model results were compared with neutralization assay data measured at a number of different time points collected from each of two patients infected with HIV-1.6
 
Based on the results derived from the model, Dr. Nourmohammad and colleagues stated that the, "... dynamics between antibodies and viruses produce a characteristic signature of co-evolution in our model, i.e., viruses are resistant to antibodies from the past and are susceptible to antibodies from the future." These results were recapitulated in the HIV patient assessment, as viruses measured at a given time point were neutralized by antibodies of later time, and they were resistant to the antibodies of the past.
 
When asked about her thoughts on the study as a whole, Dr. Nourmohammad told Contagion™, "The work is a theoretical attempt to understand the complex co-evolutionary dynamics that occur between diverse cellular populations of pathogens and the adaptive immune system during chronic infections within an individual. We mainly focused on rapidly evolving HIV viruses and neutralizing antibody-secreting B-cell repertoire: B-cells are activated and proliferate if they bind well to viral antigens, and the viruses survive by escaping this immunity. This is a rapid evolutionary arms race that occurs within a patient. Using our model, we identified key immune and viral parameters that are predictive of this co-evolutionary dynamics, and we proposed experimental measurements to estimate them." Dr. Nourmohammad also noted that, "Specifically, we characterize the conditions that favor the emergence of broadly neutralizing antibodies, which could neutralize most strains that arise in the viral population, and therefore, may have implications for vaccine design against HIV. In particular, we showed that broadly neutralizing antibodies are more likely to dominate in response to a highly diverse viral population, such as during the late stages of chronic infections. "
 
Regarding the broader implications of the study’s results, Dr. Nourmohammad told Contagion, "Our model is not a prescription for a HIV vaccine, but provides a theoretical guidance for how a 'generalist' broadly neutralizing antibody may dominate the immune response by outcompeting the 'specialist' neutralizing antibodies. While our analysis focused on HIV-immune co-evolution, our theoretical framework is general enough to apply to other out-of-equilibrium co-evolutionary scenarios, such as bacteria-phage interactions, or co-evolution of influenza virus in the context of the evolving global immune system."
 
William Perlman, PhD, CMPP is a former research scientist currently working as a medical/scientific content development specialist. He earned his BA in Psychology from Johns Hopkins University, his PhD in Neuroscience at UCLA, and completed three years of postdoctoral fellowship in the Neuropathology Section of the Clinical Brain Disorders Branch of the National Institute of Mental Health.
 
References
  1. Nourmohammad A, Otwinowski J, Plotkin JB. Host-Pathogen Coevolution and the Emergence of Broadly Neutralizing Antibodies in Chronic Infections. PLoS Genet. 2016;12: e1006171.
  2. Wang S, Mata-Fink J, Kriegsman B, et al. Manipulating the selection forces during affinity maturation to generate cross-reactive HIV antibodies. Cell. 2015;160:785–797.
  3. Childs LM, Baskerville EB, Cobey S. Trade-offs in antibody repertoires to complex antigens. Philos Trans R Soc Lond B Biol Sci. 2015;370. pii: 20140245. doi: 10.1098/rstb.2014.0245.
  4. Luo S, Perelson AS. The challenges of modelling antibody repertoire dynamics in HIV infection. Philos Trans R Soc Lond B Biol Sci. 2015;370. pii: 20140247. doi: 10.1098/rstb.2014.0247.
  5. Luo S, Perelson AS. Competitive exclusion by autologous antibodies can prevent broad HIV-1 antibodies from arising. Proc Natl Acad Sci USA. 2015;112:11654–11659.
  6. Richman DD, Wrin T, Little SJ, Petropoulos CJ. Rapid evolution of the neutralizing antibody response to HIV type 1 infection. Proc Natl Acad Sci U S A. 2003;100:4144–4149.
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