We believe that AIDS vaccine efficacy studies in primate models should involve mucosal challenge with R5 strains, preferably SHIV constructs because of the added advantage of directly testing anti-HIV-1 Env responses. To reflect the heterogeneity of the many HIV-1 quasispecies circulating in human populations, vaccine and challenge virus should not be exact matches in primate studies; ideally, AIDS vaccine efficacy studies should employ a fully heterologous challenge virus, rather than one differing only in Env. This may require the construction of SHIV strains based upon SIV backbones that differ from SIVmac239. Lastly, replacing standard single high-dose viral challenges with repeated low-dose mucosal exposures has shown promise. Ultimately, efficacy data generated in primate models through this new approach need to be compared directly with phase III clinical vaccine trials for validation.
"Initially, we examined available saliva samples from a cohort of twelve pig-tailed macaques that were part of an experimental SIV vaccination study (Polacino et al., 2008). While these macaques had undergone different vaccination protocols, they had all been challenged with SHIV (Vlasak and Ruprecht, 2006). Four to six years post challenge the macaques were still healthy, with five showing evidence for a low level ongoing SHIV infection, while the remaining seven animals showed no evidence of SHIV in plasma samples. "
[Show abstract][Hide abstract] ABSTRACT: Human herpesvirus-6 (HHV-6) and -7 (HHV-7) are Roseoloviruses within the Betaherpesvirus family, which have a high prevalence and suspected involvement in a number of diseases. Using CODEHOP-based PCR, we identified homologs of both viruses in saliva of pig-tailed macaques, provisionally named MneHV-6 and MneHV-7. This finding supports the existence of two distinct Roseolovirus lineages before the divergence of humans and macaques. Using specific qPCR assays, high levels of MneHV-6 and MneHV-7 DNA were detected in macaque saliva, although the frequency was greater for MneHV-7. A blood screen of 283 macaques revealed 10% MneHV-6 DNA positivity and 25% MneHV-7 positivity, with higher prevalences of MneHV-6 in older females and of MneHV-7 in younger males. Levels of MneHV-6 were increased in animals coinfected with MneHV-7, and both viruses were frequently detected in salivary gland and stomach tissues. Our discovery provides a unique animal model to answer unresolved questions regarding Roseolovirus pathology.
"As it is unlikely that any AIDS vaccine recipient will be exposed to an HIV variant exactly matching the immunogens, vaccine efficacy needs to be evaluated using heterologous challenge viruses . Accordingly, we challenged our cohort of Rev-Ind Nef¯SIV-vaccinated RMs with multiple low-dose mucosal exposures of SIVsmE660 as outlined in Figure 1. "
[Show abstract][Hide abstract] ABSTRACT: Rhesus macaques (RMs) inoculated with live-attenuated Rev-Independent Nef¯ simian immunodeficiency virus (Rev-Ind Nef¯SIV) as adults or neonates controlled viremia to undetectable levels and showed no signs of immunodeficiency over 6-8 years of follow-up. We tested the capacity of this live-attenuated virus to protect RMs against pathogenic, heterologous SIVsmE660 challenges.
Three groups of four RM were inoculated with Rev-Ind Nef¯SIV and compared. Group 1 was inoculated 8 years prior and again 15 months before low dose intrarectal challenges with SIVsmE660. Group 2 animals were inoculated with Rev-Ind Nef¯SIV at 15 months and Group 3 at 2 weeks prior to the SIVsmE660 challenges, respectively. Group 4 served as unvaccinated controls. All RMs underwent repeated weekly low-dose intrarectal challenges with SIVsmE660. Surprisingly, all RMs with acute live-attenuated virus infection (Group 3) became superinfected with the challenge virus, in contrast to the two other vaccine groups (Groups 1 and 2) (P=0.006 for each) and controls (Group 4) (P=0.022). Gene expression analysis showed significant upregulation of innate immune response-related chemokines and their receptors, most notably CCR5 in Group 3 animals during acute infection with Rev-Ind Nef¯SIV.
We conclude that although Rev-Ind Nef¯SIV remained apathogenic, acute replication of the vaccine strain was not protective but associated with increased acquisition of heterologous mucosal SIVsmE660 challenges.
PLoS ONE 09/2013; 8(9):e75556. DOI:10.1371/journal.pone.0075556 · 3.23 Impact Factor
"In the context of vaccine efficacy in humans, only the RV144 trial showed promising results so far  and recent follow-up studies identified vaccine-induced correlates of protection [4,5]. Additionally, biologically relevant non-human primate (NHP) models are used in HIV-1/AIDS research to gain information about vaccine-induced immunity [6,7]. In contrast to clinical studies in humans, NHPs can be deliberately challenged with well characterized virus inocula. "
[Show abstract][Hide abstract] ABSTRACT: We addressed the question whether live-virus challenges could alter vaccine-induced antibody (Ab) responses in vaccinated rhesus macaques (RMs) that completely resisted repeated exposures to R5-tropic simian-human immunodeficiency viruses encoding heterologous HIV clade C envelopes (SHIV-Cs).
We examined the Ab responses in aviremic RMs that had been immunized with a multi-component protein vaccine (multimeric HIV-1 gp160, HIV-1 Tat and SIV Gag-Pol particles) and compared anti-Env plasma Ab titers before and after repeated live-virus exposures. Although no viremia was ever detected in these animals, they showed significant increases in anti-gp140 Ab titers after they had encountered live SHIVs. When we investigated the dynamics of anti-Env Ab titers during the immunization and challenge phases further, we detected the expected, vaccine-induced increases of Ab responses about two weeks after the last protein immunization. Remarkably, these titers kept rising during the repeated virus challenges, although no viremia resulted. In contrast, in vaccinated RMs that were not exposed to virus, anti-gp140 Ab titers declined after the peak seen two weeks after the last immunization. These data suggest boosting of pre-existing, vaccine-induced Ab responses as a consequence of repeated live-virus exposures. Next, we screened polyclonal plasma samples from two of the completely protected vaccinees by peptide phage display and designed a strategy that selects for recombinant phages recognized only by Abs present after -- but not before -- any SHIV challenge. With this "subtractive biopanning" approach, we isolated V3 mimotopes that were only recognized after the animals had been exposed to live virus. By detailed epitope mapping of such anti-V3 Ab responses, we showed that the challenges not only boosted pre-existing binding and neutralizing Ab titers, but also induced Abs targeting neo-antigens presented by the heterologous challenge virus.
Anti-Env Ab responses induced by recombinant protein vaccination were altered by the multiple, live SHIV challenges in vaccinees that had no detectable viral loads. These data may have implications for the interpretation of "vaccine only" responses in clinical vaccine trials.
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