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The variant proteins, known as the<jats:italic>P. knowlesi<\/jats:italic>Schizont Infected Cell Agglutination (SICA) antigens and the<jats:italic>P. falciparum<\/jats:italic>Erythrocyte Membrane Protein 1 (PfEMP1) antigens, expressed by the<jats:italic>SICAvar<\/jats:italic>and<jats:italic>var<\/jats:italic>multigene families, respectively, have been studied for over 30 years. Expression of the SICA antigens in<jats:italic>P. knowlesi<\/jats:italic>requires a splenic component, and specific antibodies are necessary for variant antigen switch events<jats:italic>in vivo<\/jats:italic>. Outstanding questions revolve around the role of the spleen and the mechanisms by which the expression of these variant antigen families are regulated. Importantly, the longitudinal dynamics and molecular mechanisms that govern variant antigen expression can be studied with<jats:italic>P. knowlesi<\/jats:italic>infection of its mammalian and vector hosts. Synchronous infections can be initiated with established clones and studied at multi-omic levels, with the benefit of computational tools from systems biology that permit the integration of datasets and the design of explanatory, predictive mathematical models. Here we provide an historical account of this topic, while highlighting the potential for maximizing the use of<jats:italic>P. knowlesi<\/jats:italic>\u2013 macaque model systems and summarizing exciting new progress in this area of research.<\/jats:p>","DOI":"10.1017\/s0031182017001135","type":"journal-article","created":{"date-parts":[[2017,7,17]],"date-time":"2017-07-17T04:50:46Z","timestamp":1500267046000},"page":"85-100","update-policy":"https:\/\/doi.org\/10.1017\/policypage","source":"Crossref","is-referenced-by-count":31,"title":["<i>Plasmodium knowlesi:<\/i>a superb<i>in vivo<\/i>nonhuman primate model of antigenic variation in malaria"],"prefix":"10.1017","volume":"145","author":[{"given":"M. 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