ABSTRACT
UNLABELLED: The development of a vaccine that can induce high titers of functional antibodies against HIV-1 remains a high priority. We have developed an adjuvant based on an oil-in-water emulsion that incorporates Toll-like receptor (TLR) ligands to test whether triggering multiple pathogen-associated molecular pattern receptors could enhance immunogenicity. Compared to single TLR agonists or other pairwise combinations, TLR7/8 and TLR9 agonists combined were able to elicit the highest titers of binding, neutralizing, and antibody-dependent cellular cytotoxicity-mediating antibodies against the protein immunogen, transmitted/founder HIV-1 envelope gp140 (B.63521). We further found that the combination of TLR7/8 and TLR9 agonists was associated with the release of CXCL10 (IP-10), suggesting that this adjuvant formulation may have optimally stimulated innate and adaptive immunity to elicit high titers of antibodies. IMPORTANCE: Combining TLR agonists in an adjuvant formulation resulted in higher antibody levels compared to an adjuvant without TLR agonists. Adjuvants that combine TLR agonists may be useful for enhancing antibody responses to HIV-1 vaccines.
Subject(s)
HIV Antibodies/immunology , HIV Infections/immunology , HIV-1/immunology , Toll-Like Receptor 7/agonists , Toll-Like Receptor 8/agonists , Toll-Like Receptor 9/agonists , env Gene Products, Human Immunodeficiency Virus/immunology , Adjuvants, Immunologic/administration & dosage , Animals , Female , HIV Infections/virology , HIV-1/genetics , Humans , Immunization , Ligands , Macaca mulatta , Male , Toll-Like Receptor 7/immunology , Toll-Like Receptor 8/immunology , Toll-Like Receptor 9/genetics , Toll-Like Receptor 9/immunology , env Gene Products, Human Immunodeficiency Virus/administration & dosage , env Gene Products, Human Immunodeficiency Virus/geneticsABSTRACT
A major challenge for the development of a highly effective AIDS vaccine is the identification of mechanisms of protective immunity. To address this question, we used a nonhuman primate challenge model with simian immunodeficiency virus (SIV). We show that antibodies to the SIV envelope are necessary and sufficient to prevent infection. Moreover, sequencing of viruses from breakthrough infections revealed selective pressure against neutralization-sensitive viruses; we identified a two-amino-acid signature that alters antigenicity and confers neutralization resistance. A similar signature confers resistance of human immunodeficiency virus (HIV)-1 to neutralization by monoclonal antibodies against variable regions 1 and 2 (V1V2), suggesting that SIV and HIV share a fundamental mechanism of immune escape from vaccine-elicited or naturally elicited antibodies. These analyses provide insight into the limited efficacy seen in HIV vaccine trials.
