One thing that we learned in

One thing that we learned in the presented ZIKV vaccine studies is that the yield of production of the ZIKV envelope E subunit protein was very low in the current format. This finding, also confirmed by a recently published ZIKV vaccine study (Larocca et al., 2016), is similar to what was previously observed for other flaviviruses (Taylor et al., 2016). The low yield of E protein is probably due to the absence of preM, which is important for protein stability. For instance, buy thip of WNV E protein alone showed proteolytic cleavage compared to the E protein produced in the presence of preM (Taylor et al., 2016). Thus, the inclusion of preM sequence seems to be an important prerequisite in ZIKV E-based vaccine development. Importantly, in this study, we used an immunocompetent mouse challenge model of ZIKV infection. This approach was inspired by a 1952 publication (Dick et al., 1952) in which ZIKV was shown to be pathogenic in newborn mice. Although this model does not recapitulate the ZIKV pathogenesis observed in humans, it is an effective model to evaluate the in vivo neutralizing activity of vaccine-induced ZIKV immunity. During the conduct of these experiments, many mouse models of ZIKV infection were established in interferon receptor-deficient mice and SJL mice (Cugola et al., 2016; Shah and Kumar, 2016; Miner et al., 2016; Dowall et al., 2016; Lazear et al., 2016; Rossi et al., 2016). Further investigations in SJL mice, the closest clinical model of fetal microcephaly, will be considered to evaluate the efficiency of vaccine candidates here in the future. The following are the supplementary data related to this article.
Conflict of Interest Statement
Author Contributions
Acknowledgments & Funding We thank Ms. Christine Heiner for her assistance with manuscript preparation. We are grateful to Dr. Rober Tesh at the University of Texas Medical Branch for providing the Zika DAKAR41542 strain. UPMC and the UPMC/University of Pittsburgh Department of Surgery provided funding to support these preliminary studies.
Introduction Treatment with combination antiretroviral therapy (ART) has increased the lifespans of persons infected with the human immunodeficiency virus (HIV) (Antiretroviral Therapy Cohort, C, 2008; Mills et al., 2011); however, immune activation and chronic inflammation have been shown to persist in spite of suppressed viral replication (Funderburg, 2014; Deeks et al., 2013; Hunt et al., 2014; Lederman et al., 2011). Several soluble markers of immune activation and inflammation, including interleukin-6 (IL-6) (Hunt et al., 2014; Sandler et al., 2011; Longenecker et al., 2014), high-sensitivity C-reactive protein (hsCRP), and tumor necrosis factor α receptor I (sTNFR-I) (Hunt et al., 2014; Tenorio et al., 2015; Kalayjian et al., 2010) are associated with all-cause mortality (Kalayjian et al., 2010 and Kuller et al., 2008) and deaths related to cardiovascular disease (CVD) (Duprez et al., 2012) in HIV-infected individuals (Tenorio et al., 2015). Soluble markers of monocyte and macrophage activation (sCD14 or sCD163) are also associated with mortality (Hunt et al., 2014 and Sandler et al., 2011), coronary calcium levels (Longenecker et al., 2014), and unstable coronary plaques (Burdo et al., 2011) in this population. Comparing the levels of immune activation and inflammation after the initiation of different ART regimens can provide additional information about the effectiveness of the regimens beyond virologic suppression. Antiretroviral therapy regimens most commonly include two nucleoside reverse transcription inhibitors (NRTIs) and a third drug from a different class. Tenofovir disoproxil fumarate (TDF) (National Center for Biotechnology Information, n.d.-a, CID=6,398,764) is a potent and well-tolerated NRTI recommended by all major treatment guidelines (Panel on Antiretroviral Guidelines for Adults and Adolescents, 2015; Huldrych et al., 2014; European AIDS Clinical Society, 2015), but is also associated with greater nephrotoxicity (Hall et al., 2011; Gupta, 2008; Post et al., 2010) and bone mineral density loss (Stellbrink et al., 2010; Schafer et al., 2013; McComsey et al., 2011) than other nucleoside or nucleotide reverse transcriptase inhibitors. TDF is a prodrug that is metabolized to tenofovir (TFV), which is diphosphorylated intracellularly to its active metabolite, TFV diphosphate (TFV-DP). Higher circulating plasma TFV levels have been associated with the renal and bone effects of TDF (Van Rompay et al., 2008).