Consistent with our overall assertion that serotype

Consistent with our overall assertion that serotype-specific, conserved, and cross-reactive T thapsigargin all can contribute to protection against DENV infection, phase 2b and 3 trials of Sanofi\'s DENV-yellow fever virus (YFV) chimeric vaccine showed limited efficacy depending on the serotype and host immune status (Guy et al., 2015; Guy and Jackson, 2016; Hadinegoro et al., 2015; Halstead and Russell, 2016). In particular, the Sanofi vaccine contains YFV but not DENV NS proteins, which are the major targets of the anti-DENV CD8 T cell response (Weiskopf et al., 2013), suggesting that the absence of the vaccine-induced DENV-specific CD8 T cell response may be responsible for the lack of robust protection observed in the Sanofi clinical trials. In comparison with the Sanofi vaccine, the other two leading vaccine candidates developed by NIH and Takeda are also live-attenuated viruses, but are not chimeric of two different flaviviruses. The NIH and Takeda vaccine candidates represent only DENV, and thus contain DENV NS proteins. However, the NIH tetravalent vaccine formulation contains NS proteins from 3 DENV serotypes, while the Takeda tetravalent formulation consists of NS proteins from only 1 DENV serotype. Phase 1 trials have shown that both the NIH and Takeda vaccine can induce DENV-specific T cell responses (Weiskopf et al., 2014; Chu et al., 2015). While the NIH vaccine-induced CD8 T response in phase 1 participants focused on conserved epitopes (i.e. identical in >1 serotype) (Weiskopf et al., 2014), the specificity of the Takeda vaccine-induced CD8 T cell response is as yet to be fully defined and may differ from the NIH vaccine by targeting DENV2 serotype-specific, conserved, and cross-reactive epitopes. Our finding that cross-reactive T cells with even low avidity and magnitude can limit viral burden in mice imply that both NIH and Takeda vaccines may show good efficacy in phase 2 and 3 trials. In summary, our results emphasize that a DENV vaccine should elicit not only Ab but also CD8 T cell responses to maximize efficacy.
Conclusion
Conflict of Interest Statement
Author Contributions
Acknowledgements
Introduction Early in HIV research it was demonstrated that pro-inflammatory cytokines, in particular TNF, drive HIV replication and pathogenesis (Reddy et al., 1988; Fauci, 1996). However, despite efficient ART, TNF plasma levels remain elevated and soluble forms of the TNF receptors (TNFR-I and II) even increase (Aukrust et al., 1999; Wada et al., 2015). As both, proTNF cleavage and TNFR shedding, require the activation of TNF-alpha converting enzyme (TACE/ADAM17), the activation of this protease seems at least in part unaffected by ART. Reaffirming a role of TNF in chronic HIV infection, treatment with TNF inhibitors improves CD4 counts and reduces immune activation (Gallitano et al., 2016; Kumar et al., 2013). To explain chronic immune activation, it is suggested that direct and indirect effects of the infection, as for example microbial translocation, viral co-infections and HIV expression itself including exosomal TAR RNA, stimulate the innate immune sensing system leading to immune cell stimulation and TNF production (Sandler and Douek, 2012; Iwasaki, 2012; Lawn, 2004; Sampey et al., 2016). In addition a direct stimulation of cytokine production has been reported for Vpr, Tat and Nef, however, most of these studies were done with recombinant viral proteins (Kumar et al., 2013). Since viral replication is greatly reduced in chronic infection, current concepts do not consider a major role of viral proteins in persistent immune activation. This includes the viral Nef protein, an essential cofactor of HIV replication in vivo (Gorry et al., 2007). Therefore, the role of Nef appears to be restricted to augment viral replication in a yet poorly understood manner that seems to include receptor trafficking and stimulation of T cell signaling (Abraham and Fackler, 2012; Baur, 2011).