Improved Vaccine Protection from Simian AIDS by the Addition of Nonstructural Simian Immunodeficiency Virus Genes

Abstract

An HIV-1 vaccine able to induce broad CD4+ and CD8+ T cell responses may provide long-term control of viral replication. In this study we directly assess the relative benefit of immunization with vaccines expressing three structural Ags (Gag, Pol, and Env), three early regulatory proteins (Rev, Tat, and Nef), or a complex vaccine expressing all six Ags. The simultaneous administration of all six Ags during vaccination resulted in Ag competition manifested by a relative reduction of CD8+ T cell and lymphoproliferative responses to individual Ags. Despite the Ag competition, vaccination with all six Ags resulted in a delay in the onset and a decrease in the extent of acute viremia after mucosal challenge exposure to highly pathogenic SIVmac251. Reduced levels of acute viremia correlated with lower post-set point viremia and long-term control of infection. In immunized animals, virus-specific CD4+ T cell and lymphoproliferative responses were preserved during acute viremia, and the maintenance of these responses predicted the long-term virological outcome. Taken together, these results suggest that the breadth of the immune response is probably more important than high frequency responses to a limited number of epitopes. These data provide the first clear evidence of the importance of nonstructural HIV Ags as components of an HIV-1 vaccine.

Immune-response profiles induced by human immunodeficiency virus type 1 vaccine DNA, protein or mixed-modality immunization: increased protection from pathogenic simian–human immunodeficiency virus viraemia with protein/DNA combination

“…These results suggest an important role for Nef and Gag cellular immune responses that appear to be driven by virus replication in the early phase of the infection. Similar results have been reported for anamnestic responses against Gag (Dale et al, 2004;Hel et al, 2006). However, for SIV Gag, pre-challenge, vaccineinduced responses were also found to correlate with suppression of virus replication when a DNA prime/ Nef-, SIV mac Nef-and SIV mac Gag-stimulated wells, per million PBMCs measured either 6 weeks after the fourth (last) immunization or 2 weeks after challenge, as well as the individual SIV Nef-and SIV Gag-specific IFN-c ELISpot responses measured 2 weeks after challenge, are plotted against the steadystate plasma virus load, measured 28 weeks after challenge.…”

“…DNA vaccines were shown to induce both humoral and cellular immune responses in rodents, but in non-human primates and in humans, only low-level immunogenicity has been reported (Estcourt et al, 2004;Robinson, 1999). Efforts have been directed at improving these responses by boosting with viral vectors (Amara et al, 2002;Brave et al, 2007;Casimiro et al, 2005;Doria-Rose et al, 2003;Hel et al, 2006;Koopman et al, 2004;Letvin et al, 2004). DNA vaccines are generally effective at stimulating CD8 responses, whilst subunit vaccines are more effective at eliciting antibody responses (Barouch et al, 2000;Earl et al, 2001Earl et al, , 2002Patterson et al, 2004;Robinson, 1999).…”

“…Strategies to improve the efficacy of HIV-1 Env singlecomponent vaccines have been directed at inclusion of gag/ pol structural and/or tat, rev and nef regulatory gene products (Calarota et al, 1998;Hel et al, 2006;Stittelaar et al, 2002;Wilson et al, 2006). Whilst immunization with simian immunodeficiency virus (SIV) Gag, alone or in combination with HIV-1 Env or Nef and Tat, has already yielded promising results, the data must be interpreted with caution as, in most cases, Mamu A*01-positive animals, which mount a particularly robust response to highly conserved Gag peptides, were used (Amara et al, 2001(Amara et al, , 2002Barouch et al, 2001;Casimiro et al, 2005;Egan et al, 2004;Montefiori et al, 1996;Mooij et al, 2004;Seth et al, 2000;Shiver et al, 2002).…”

Comparative study of Tat vaccine regimens in Mauritian cynomolgus and Indian rhesus macaques: Influence of Mauritian MHC haplotypes on susceptibility/resistance to SHIV89.6P infection

“…Tat combined with other HIV antigens might better confer protection at higher challenge doses. Immunizations with Tat plus Rev and Tat plus other nonstructural HIV gene products have shown protection against SIV [45,46]. A potential synergy between Tat and Env leading to enhanced protective efficacy in rhesus macaques against SHIV 89.6P was recently reported [44].…”

“…The significantly higher peak Tat-specific T cell proliferative responses seen in vaccinated macaques with the resistant haplotypes prior to challenge suggest cellular immunity should be further explored as a possible mechanism for the observed resistance. Results of the haplotype analysis and vaccine evaluations, together with reports showing that vaccines targeting Tat in combination with other viral proteins elicit good protective efficacy in non-human primates [44][45][46], suggest that HIV Tat vaccines might be best exploited in combination with other viral antigens.…”