Plasmodium falciparum-encoded variant surface antigens (VSA) are expressed on the surface of infected erythrocytes (IE) and mediate binding to a range of endothelial cell receptors [
1]. Endothelial adhesion contributes to the particular virulence of the
P. falciparum and most likely has evolved as a mechanism to avoid parasite clearance in the spleen [
2‐
4]. Individuals living in areas of intense parasite transmission develop immunity towards severe malaria early in life [
5]. Parasites causing severe malaria in young children with limited pre-existing immunity tend to express a limited, relatively conserved subset of VSA (VSA
SM) that is more often and better recognized by antibodies from most parasite-exposed individuals than the larger and more diverse VSA
UM subset expressed by parasites causing uncomplicated malaria [
6‐
8]. It thus appears that expression of VSA
SM confers a selective advantage in non-immune individuals, perhaps by allowing particularly efficacious endothelial sequestration and consequently high effective growth rates. The best characterized VSA are the
var gene-encoded
P. falciparum erythrocyte membrane protein 1 (PfEMP1) family [
9‐
11]. Each haploid parasite genome contains 50–60
var genes, of which the 59
var genes annotated in the fully sequenced
P. falciparum clone 3D7 can be divided into three major groups, A, B and C, based on sequence analysis [
12,
13]. The functional relevance of this grouping is supported by the parallel differences in CD36-binding characteristics of PfEMP1 CIDR1α domains. Thus, GroupA CIDR1α domains do not bind CD36, whereas CIDR1α domains encoded by GroupB and GroupC
var genes do [
14]. The 3D7 PfEMP1 repertoire may well represent the VSA
UM -VSA
SM spectrum observed in field isolates, and recent findings point to GroupA as encoding VSA
SM-type PfEMP1 molecules in patient isolates [
13,
15‐
17]. Unfortunately, little is known about
var gene expression
in vivo, and studies have been frustrated by the difficulties in detecting and quantifying expression in parasites with unknown
var gene repertoires. This difficulty has been overcome by taking advantage of the knowledge of the
var gene repertoire in 3D7 and analyzing
var gene expression in NF54 parasites (the parental line of 3D7) isolated from non-immune individuals experimentally infected by mosquito challenge. Immediately upon release from the liver, the parasites appeared to transcribe all
var genes, with GroupA genes being the least transcribed. However, within one or two parasite generations this pattern changed, in particular in those parasites exhibiting the fastest
in vivo growth rates. Here, only a few genes dominated the
var transcript population. The data indicate that PfEMP1-determined differences in growth rates shape the expressed PfEMP1 repertoire, and that some PfEMP1 variants confer high effective parasite multiplication rates in non-immune individuals.