It will be of interest to revisit such non-human primate studies at the molecular level and compare var gene expression profiles in monkeys with and without the spleen present. We would predict a similar outcome as shown here for SICAvar expression: full-length var transcripts evident on northern blots from intact monkeys but not after passage in splenectomized animals. Such studies would also be valuable with P. coatneyi, a simian malaria parasite that is closely related to P. knowlesi, but which Tulathromycin B expresses ‘knobs’ and characteristics of cytoadherence and deep vascular sequestration like P. falciparum, reviewed in 1,20,55,56. Plasmodium coatneyi has a large multigene family with multiexon structural features similar to the SICAvar genes and may be similarly regulated in macaques. Plasmodium fragile is likely to have a similar family, based on prior knowledge of antigenic variation in this related simian malaria species. The strategic use and comparison of these various in vivo nonhuman primate models may facilitate our understanding of P. falciparum var gene expression, regulation, and pathogenesis. Interestingly, preliminary evidence is also materializing to show that placental tissue may be important to regulate the expression of P. falciparum var genes that are expressed during pregnancy. In light of our data showing many transcript sequences are produced in SICA parasites, without all of them necessarily being translated, the data of Wang et al. 2009 is intriguing. This group has reported the detection of var transcripts representing 90% of the var gene family in the blood of a malaria naive vaccine trial volunteer who had been infected with P. falciparum, NF54 strain sporozoites. This study and its interpretation could appear contrary to the basic tenet of antigenic variation and immune evasion; i.e., that mechanisms are in place to prevent the expression of all but one variant protein from the family at the same time. Wang and others suggested that the parasite population may express most or all var genes early on in an infection and that selection defined by cytoadherence to receptors or adhesion-blocking antibodies may then take place to ultimately result in the mutually exclusive expression of specific var types. It remains unclear how such selection processes would Mepiroxol become limited to the expression of one PfEMP1 when the family shares various combinations of cysteine-rich domains, many with common adhesive characteristics, reviewed in 60. It also remains unknown how switches would then occur over time to develop chronic infections, characteristic of the process of antigenic variation and predicted to involve both inducing and opsonizing antibodies. Based on the original studies and ongoing data coming from the P. knowlesi model system, we again put forth the alternative and potentially complementary view that most if not all SICAvar genes are transcribed and certain genes become upregulated in the host blood-stage infection, as a rule, but that the majority of the transcripts are then silenced, leaving only those that are destined to be translated as intact messages. This possibility, which would prevent the rapid expression and exposure of the variant family to the immune system, had been proposed by Piet Borst as one option for how P. falciparum may control expression of the var multigene family and its proteins. With this scenario, along with splenic factors that determine the state of gene expression. More recent reviews by Piet Borst reflect upon various mechanistic possibilities and many questions still in need of answers for Plasmodium and other organisms.