Mucosal Priming of Simian Immunodeficiency Virus-Specific Cytotoxic T-Lymphocyte Responses in Rhesus Macaques by theSalmonellaType III Secretion Antigen Delivery System

Abstract

Nearly all human immunodeficiency virus (HIV) infections are acquired mucosally, and the gut-associated lymphoid tissues are important sites for early virus replication. Thus, vaccine strategies designed to prime virus-specific cytotoxic T lymphocyte (CTL) responses that home to mucosal compartments may be particularly effective at preventing or containing HIV infection. The Salmonella type III secretion system has been shown to be an effective approach for stimulating mucosal CTL responses in mice. We therefore tested ⌬phoP-phoQ attenuated strains of Salmonella enterica serovar Typhimurium and S. enterica serovar Typhi expressing fragments of the simian immunodeficiency virus (SIV) Gag protein fused to the type III-secreted SopE protein for the ability to prime virus-specific CTL responses in rhesus macaques. Mamu-A*01 ؉ macaques were inoculated with three oral doses of recombinant Salmonella, followed by a peripheral boost with modified vaccinia virus Ankara expressing SIV Gag (MVA Gag). Transient low-level CTL responses to the Mamu-A*01 Gag 181-189 epitope were detected following each dose of Salmonella. After boosting with MVA Gag, strong Gag-specific CTL responses were consistently detected, and tetramer staining revealed the expansion of Gag 181-189 -specific CD8 ؉ T-cell responses in peripheral blood. A significant percentage of the Gag 181-189 -specific T-cell population in each animal also expressed the intestinal homing receptor ␣4␤7. Additionally, Gag 181-189 -specific CD8 ؉ T cells were detected in lymphocytes isolated from the colon. Yet, despite these responses, Salmonella-primed/MVA-boosted animals did not exhibit improved control of virus replication following a rectal challenge with SIVmac239. Nevertheless, this study demonstrates the potential of mucosal priming by the Salmonella type III secretion system to direct SIV-specific cellular immune responses to the gastrointestinal mucosa in a primate model.

Protection against Mucosal Simian Immunodeficiency Virus SIV mac251 Challenge by Using Replicating Adenovirus-SIV Multigene Vaccine Priming and Subunit Boosting

“…Our results show clearly that priming with Ad5hr-SIVenv/rev and boosting with gp120 was not sufficient to protect against SIV mac251 rectal challenge but that additional priming with either Ad5hr-SIVgag and/or Ad5hr-SIV nef⌬ [1][2][3][4][5][6][7][8][9][10][11][12][13] resulted in significant and similar extents of viremia control. Protective effects seen in group II, III, and IV macaques were not restricted to viremia reduction, but extended to survival times.…”

“…As outlined in Table 1, five groups of seven to eight macaques each were primed at week 0 intranasally and orally and at week 12 intratracheally with Ad5hr-SIV smH4 env/rev alone, with the Ad5hr-SIVenv/rev recombinant plus Ad5hr-SIV mac239 gag or Ad5hr-SIV mac239 nef⌬ [1][2][3][4][5][6][7][8][9][10][11][12][13] , or with all three recombinants (5 ϫ 10 8 PFU/recombinant). A sixth control group was given empty E3-deleted Ad5hr vector.…”

“…Unlike HIV transmission, where CCR5-using strains predominate, SHIV 89.6P uses CXCR4 and is highly sensitive to neutralization with autologous antibodies. With the exception of live attenuated SIV vaccines able to confer complete protection (7) but with associated safety concerns (38), current strategies have not provided equivalent protection against more vigorous SIV strains with greater relevance to HIV infection, including uncloned SIV mac251 (4,19,28,30), cloned SIV mac239 (10,15), SIVsmE660 (8,9,29) and SIVsmDeltaB670 (12). Strong protection against SIV mac251 intrarectal challenge was reported in one study (2), but similar protective efficacy was not achieved subsequently (13).…”

“…Strong persistent control of viral replication was not achieved, however. We modified the immunization regimen and added Ad5hr-SIV nef⌬ [1][2][3][4][5][6][7][8][9][10][11][12][13] to the vaccine strategy. Priming with these Ad5hr-SIV recombinants elicited potent cellular immunity to all four encoded SIV genes: env, rev, gag, and nef.…”

Bacterial vectors for active immunotherapy reach clinical and industrial stages

“…Therefore, this strategy is an effective way to deliver antigens directly inside APCs. [5][6][7][8][9] earliest non-surgical cancer treatment. In the nineteenth century, William Coley developed the first bacterial-based cancer treatment, which was composed of killed gram-positive streptococci and gram-negative Serratia marcescens injected directly into the tumor.…”