ABSTRACT
Studies have shown that vaccine vectors and route of immunization can differentially activate different arms of the immune system. However, the effects of different HIV vaccine immunogens on mucosal inflammation have not yet been studied. Because mucosal sites are the primary route of HIV infection, we evaluated the cervico-vaginal inflammatory cytokine and chemokine levels of Mauritian cynomolgus macaques following immunization and boost using two different SIV vaccine immunogens. The PCS vaccine delivers 12 20-amino acid peptides overlapping the 12 protease cleavage sites, and the Gag/Env vaccine delivers the full Gag and full Env proteins of simian immunodeficiency virus. We showed that the PCS vaccine prime and boosts induced short-lived, lower level increases of a few pro-inflammatory/chemotactic cytokines. In the PCS-vaccine group only the levels of MCP-1 were significantly increased above the baseline (P = 0.0078, Week 6; P = 0.0078, Week 17; P = 0.0234; Week 51) following multiple boosts. In contrast, immunizations with the Gag/Env vaccine persistently increased the levels of multiple cytokines/chemokines. In the Gag/Env group, higher than baseline levels were consistently observed for IL-8 (P = 0.0078, Week 16; P = 0.0078, Week 17; P = 0.0156, Week 52), IL-1ß (P = 0.0234, Week 16; P = 0.0156, Week 17; P = 0.0156, Week 52), and MIP-1α (P = 0.0313, Week 16; P = 0.0156, Week 17; P = 0.0313, Week 52). Over time, repeated boosts altered the relative levels of these cytokines between the Gag/Env and PCS vaccine group. 18 weeks after final boost with a higher dosage, IP-10 levels (P = 0.0313) in the Gag/Env group remained higher than baseline. Thus, the influence of vaccine immunogens on mucosal inflammation needs to be considered when developing and evaluating candidate HIV vaccines.
Subject(s)
Cervix Uteri/drug effects , Cytokines/metabolism , Gene Products, env/administration & dosage , Gene Products, gag/administration & dosage , Inflammation Mediators/metabolism , SAIDS Vaccines/administration & dosage , Simian Acquired Immunodeficiency Syndrome/prevention & control , Simian Immunodeficiency Virus/immunology , Vagina/drug effects , Animals , Cervix Uteri/immunology , Cervix Uteri/metabolism , Female , Gene Products, env/genetics , Gene Products, env/immunology , Gene Products, env/toxicity , Gene Products, gag/genetics , Gene Products, gag/immunology , Gene Products, gag/toxicity , Macaca fascicularis , Mucous Membrane/drug effects , Mucous Membrane/immunology , Mucous Membrane/metabolism , SAIDS Vaccines/genetics , SAIDS Vaccines/immunology , SAIDS Vaccines/toxicity , Simian Acquired Immunodeficiency Syndrome/immunology , Simian Acquired Immunodeficiency Syndrome/virology , Time Factors , Vaccination , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/genetics , Vaccines, Synthetic/immunology , Vaccines, Synthetic/toxicity , Vagina/immunology , Vagina/metabolismABSTRACT
The only vaccines shown to be protective against intravenous challenge with virulent virus in the simian immunodeficiency virus (SIV)/macaque model are attenuated live SIVs. However, these vaccines have several disadvantages: 1) they persist indefinitely in vaccinated macaques; 2) they are pathogenic to neonatal macaques; and 3) they are lethal in some adult macaques. To enhance the safety and efficacy of these vaccines, we immunized macaques first with recombinant vaccines and then inoculated the animals with SIV(delta(nef)). In the first experiment, preimmunized macaques advanced to disease slower than controls after challenge with virulent SIV; five animals survived for 3 years without disease and only the vaccine virus (SIV(delta(nef)) could be isolated at this time. In the second experiment, preimmunized animals had lower virus loads and no disease compared to controls.
