Acad

Acad. time points, a majority of the HIV-specific T cell responses, elicited by all vectors, were directed against Env, Glycyrrhetinic acid (Enoxolone) rather than Gag, determinants, as previously observed with other vector systems. Both modified vectors elicited up to 6-fold-higher frequencies of HIV-specific CD8 and CD4 T cell responses and up to 25-fold-higher titers of Env (gp120)-specific binding (nonneutralizing) antibody responses that were relatively transient in nature. While the correlates of protection against HIV infection remain incompletely defined, our results indicate that the rational deletion of specific genes from MVA vectors can positively alter their cellular and humoral immunogenicity profiles in nonhuman primates. INTRODUCTION The development of a safe and efficacious human immunodeficiency virus (HIV) vaccine remains a high priority in order to provide a sustainable solution to control the current AIDS pandemic (82). However, correlates of protection against HIV infection and disease progression remain incompletely defined and therefore pose a challenge to vaccine development with regard to defining the precise nature of protective immune responses that should be emulated through immunization (29, 31). While the generation of antibodies that exhibit broad neutralization activity against diverse HIV strains holds the promise of informing efforts to confer sterilizing immunity against HIV infection, relevant HIV envelope (Env)-derived immunogens that are capable of eliciting such broadly neutralizing antibodies in the context of Glycyrrhetinic acid (Enoxolone) immunization represent a still-unrealized vision (84). Interestingly, the RV144 efficacy trial evaluated a vaccination regimen consisting of priming with a series of recombinant canarypox virus (ALVAC-HIV) immunizations followed by boosting immunizations with recombinant gp120 (AIDSVAX-B/E) and demonstrated an overall vaccine efficacy of 31% for the reduction of HIV acquisition. Because this immunization regimen induced predominantly nonneutralizing antibodies, rather than T cell immunity, these results suggest that nonneutralizing antibodies that target the HIV envelope may contribute more to the prevention of HIV acquisition than previously appreciated (41, 68). Alternatively, the development of AIDS vaccines whose mechanism of action is predicated upon eliciting T cell responses to control HIV infection, rather than to prevent infection and has demonstrated safety and immunogenicity Glycyrrhetinic acid (Enoxolone) in BCG prime-MVA85A boost immunization strategies (10, 39, 65). However, MVA-based HIV vaccines have exhibited variable, but generally limited, immunogenicity in Glycyrrhetinic acid (Enoxolone) clinical evaluations, particularly when utilized as a single modality (22, 34, 35, 46, 47, 61, 66, 83). Several known factors contribute to this suboptimal immunogenicity profile of MVA vectors. These factors include the immunodominance of the T cell responses to the large number of vector-derived gene products over the inserted immunogen of interest as well as the generation of vector-specific neutralizing antibodies that result in a diminished capacity for effective booster immunization (16, 44, 70, 73). While prime-boost immunization regimens that utilize MVA-based vaccines in combination Glycyrrhetinic acid (Enoxolone) with heterologous vaccine vectors, such as plasmid DNA (34, 69) and recombinant adenovirus vectors (8), DTX3 can improve vaccine immunogenicity, the identification of modifications to the MVA vector itself that render these vaccines intrinsically more immunogenic than those derived from the parental MVA backbone should prove beneficial. One approach toward improving the immunogenicity of MVA-based vaccines that we have pursued is based upon the deletion of an essential viral replication gene ((5) as experimental vector modifications. We derived vaccines from the 4, 5, and parental (control) MVA backbones that express identical HIV consensus subtype C Env and Gag antigens and comparatively evaluated the cellular and humoral immune responses that were elicited by these recombinant vaccines.