The mechanism of the profound control of acute viremia canno

The mechanism of the profound control of acute viremia cannot be deduced from our observation as the animals responded rather homogenously with CD8+ T cells and not with CD4+ T cells, and we failed to recover responsive intestinal T cells pre-challenge for technical reasons. It is nevertheless worth noting that we previously observed CD8+ T cell dependent and MHC class II independent control of chronic viral infection (Holst et al., 2011), and that in the current study even the animals without directly measurable infection had recall tat, vif, rev and vpr vaccine primed T cell responses, gag specific T cell responses, and virus driven CD4+ T cell responses. These immune response patterns accurately mimics our observations during LCMV infection in inbred mice where occult infection was present, but undetectable using standard assays (Holst et al., 2015), and is similar to some of the effects observed during assumed preventive pharmacological inhibition of SHIV infection (Kersh et al. 2011; Promadej-Lanier et al. 2008; Tsegaye et al. 2015). However, unlike the LCMV studies in inbred mice where a subdominant antigen could reliably prevent exhaustion and allow the infection to raise dominant antigen specific T cells, this primate studies used randomly selected macaques. Notably, the two aviremic animals did express two of the three elite resistance associated hematoxylin present in the vaccinated cohort (A*08 and B*17), and it is possible that this is part of the explanation of the observed effect. The absence of an early peak in virus replication that we observe in infected vaccines and indeed in animals that become infected and rapidly and durably control the infection is a highly unusual finding in vaccine studies. Other studies that successfully achieved partial control of replication even with multiple log reduction in peak viremia, still exhibit an early peak replication phase with normal viral kinetics (Casimiro et al. 2005; Liu et al. 2009). This normal consistency of peak viremia also includes the much larger Barouch et al. study which observed a combination of reduced acquisition and potent post-infection viremic control of SIV mac251 (Barouch et al., 2012). While the infection progresses different in our animals as compared to other vectored vaccination attempts, the course of infection in our infected vaccinees show some resemblance to the slow progression of infection in animals infected with an ultimately unsuccessful mismatched live-attenuated vaccine (Johnson et al. 1999; Wyand et al. 1999). This could be consistent with the original hypothesis rom the mouse studies, that viremic control is maintained by an infection primed response made possible by an early vaccine induced reduction in viral replication (Holst et al., 2015), with the caveat that SIV can gradually escape most T cell responses if near complete virological suppression is not achieved, but this could not be confirmed in our trial that was too small to perform meaningful correlate analysis. The task of achieving early reduction of virus control without dominant antigen was considered daunting from the onset and this is the reason why we used the MHC class II associated invariant chain adjuvant, a heterologous virus vectored prime-boost regimens and combined mucosal and parenteral immunization together with the unusual choice of antigens. That the specific antigen choice or perhaps specific properties of the targeted antigens plays a unique role was suggested in a study by Hel et al., where a heterologous vectored virus vectored tat, rev and nef immunization was used and a small, but consistent delay in the time to reach peak viremia was reported (Hel et al. 2006). Immunizations with the tat antigen has also previously been claimed to reduce immune activation in patients on ART in prophylactic vaccination studies (Ensoli et al. 2010), and it is associated with protection against SHIV challenge in macaques (Bachler et al., 2013). However, in these cases protection was linked to antibody responses and we could not substantiate any association with tat antibodies and protection. Our vaccine did not include the dominant antigen nef and the early effects on early viral control were much greater in our study. Likely, the use of combined intramuscular and mucosal priming which allow mucosal effector cell recruitment to be maintained longer (Uddback et al., 2016), and/or the use of the MHC class II associated invariant chain as an adjuvant is responsible for the improved early control, but such causality is difficult to establish when using a repeated low-dose challenge regimen. Importantly for future studies attempting to build on our findings, the effects of the non-structural antigen vaccine in Hel et al. were additive with the structural gag-pol-nef vaccine also.(Hel et al., 2006). Thus, the ability to delay virus spread could possibly be applied to work in concert with T cells directed against other effective, but not normally very immunogenic epitopes targeting conserved regions of the HIV/SIV structural genes (Kulkarni et al. 2014; Mothe et al. 2015; Ondondo et al. 2016). When considering the future prospect of a partially effective vaccine, the absence of peak viremia is also an intriguing vaccine property in its own right. Thus, although the exact contribution of acute infection to forward transmission is unknown, epidemiological data have emerged to support a disproportionately large role, and genital mucosal secretions are considerably elevated in the weeks after acute infection (Miller et al. 2010; Pilcher et al. 2007; Volz et al. 2013). A vaccine that reduces acquisition as the RV144 trial or newer partly adenovirus based vaccines (Barouch et al., 2012; Barouch et al., 2015), as well as acute infectivity have an impact on further spread of the infection, and it would be predicted to synergize with treatment as a prevention strategy in reducing forward transmissions.