In the current study we investigated PfEMP expression in

In the current study we investigated PfEMP1 antibiotics in RBCs that had been previously cryopreserved and thawed prior to inoculation with P. falciparum. While it is possible that this approach could lead to genotype-specific artifacts, data from our laboratory using fresh RBCs and a different ICAM1 and CD36 binding laboratory-adapted parasite strain, A4U, also showed reduced PfEMP1 expression in HbS pRBC that was reversed with co-inheritance of α+thalassemia (supplementary material, Fig. S7). Therefore a consistent effect of RBC genotype on PfEMP1 expression is seen with four different P. falciparum strains, using both fresh and cryopreserved cells. In conclusion, our data suggest that the negative epistatic interaction between HbAS and α+thalassemia with regard to malaria protection that is seen at an epidemiological level might in part be explained by changes in the cytoadhesion and rosetting properties of mixed-genotype pRBCs, which might in turn relate to altered expression of PfEMP1. It remains to be tested how this relates to defects in parasite protein trafficking systems (Cyrklaff et al., 2011), and whether other important mechanisms of protection including altered knob expression on the surface of pRBCs (Cholera et al., 2008; Krause et al., 2012), enhanced immune responses (Williams et al., 2005d; Verra et al., 2007) and phagocytosis (Ayi et al., 2004) might also be attenuated in this negative interaction.
Funding This work was funded by the Wellcome Trust through Senior Research Fellowships awarded to TNW (grant no. 091758) and JAR (grant no. 084226), through core support to the KEMRI-Wellcome Trust Programme (grant no. 084535) and through a sub-grant from a Wellcome Trust Strategic Award (grant no. 084538) to DHO.
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Introduction The vaccine tested in the RV144 Thai clinical trial provided modest protection in healthy heterosexual individuals against HIV-1 infection. To date this is the only HIV clinical trial to demonstrate vaccine efficacy (VE), albeit at a level of 31.2% (Rerks-Ngarm et al., 2009). A case–control study designed to identify immune correlates of reduced infection risk demonstrated that high levels of antibodies (Abs) directed against the V1V2 region of the virus gp120 envelope glycoprotein were associated with a decreased risk of HIV-1 infection, while high levels of Env-specific plasma IgA were associated with an increased risk (Haynes et al., 2012). The V1V2 vaccine-induced Abs were shown to be broadly reactive with the V2 region of multiple subtypes despite immunization with immunogens from only subtypes B and CRF01_AE (Zolla-Pazner et al., 2013, 2014). Genetic studies that compared the V1V2 region of viruses infecting placebo and vaccine recipients identified two positions in V2, 169 and 181, that distinguished viruses from vaccine recipients, resulting in VEs of 48% and 78%, respectively (Rolland et al., 2012). This sieve analysis complemented the finding of an association between high V1V2-binding Abs and reduced HIV-1 acquisition, and provided independent evidence that vaccine-induced V2 Ab responses plausibly had a role in the reduced rate of infection associated with the RV144 vaccine regimen (Liao et al., 2013; Liu et al., 2013; Zolla-Pazner et al., 2013; Pollara et al., 2014; Yates et al., 2014). Additional analyses showed that plasma Abs from RV144 vaccinees reactive in a microarray to a linear V3 peptide from CRF01_AE were also an inverse correlate of infection risk, but only in vaccine recipients who had lower levels of Env-specific plasma IgA and aggregate neutralizing Ab activity (Gottardo et al., 2013), and V3-specific Abs from RV144 vaccinees were shown to capture infectious virions, including the vaccine strain CM244 (Liu et al., 2013). These and previous data (Karasavvas et al., 2012) generated the hypothesis that IgG Abs to epitopes in both the V2 and V3 regions of gp120 are part of a complex interplay of immune responses that contributed to the reduced rate of infection in RV144 participants, and suggested that further delineation of additional elements of the V3 Ab response might reveal important information about the factors involved in blocking HIV infection.