Identifying Critical Stages in Vaccine Induced IHIV-I Immunity The emergence of neutralizing serum antibody responses only after cellular immune responses have suppressed HIV replication has led to doubts regarding the importance of humoral immunity in controlling HIV infections. Nonetheless, rare, broadly cross-reactive antibodies are capable of neutralizing multiple isolates of HIV-1 in vitro, and when passively administered can prevent experimental infections. Thus, efficacious humoral immune responses remain crucial to the development of protective HIV-1 vaccines. Why are such antibodies rarely produced by HIV-infected patients? Why are the neutralizing epitopes present on the HIV-1 envelope so poorly immunogenic? Several explanations for the remarkable scarcity of HIV-1 broadly reactive, neutralizing antibody have been offered including the complexity and genetic plasticity of the HIV envelope antigens, the shielding of crucial antigen sites by glycosylation, competitive suppression by non-neutralizing surface antigens, immunological tolerance, and insufficient diversity in the primary antibody repertoire. All of these hypotheses are plausible, but remarkably detailed in situ studies of primary immune responses to HIV-1 antigens have not been performed. We know that HIV-1 neutralizing epitopes are poorly immunogenic but we do not know why. We shall, therefore, carry out studies to identify any deficits in the humoral responses of mice immunized with HIV-1 vaccines by focusing on the characteristic patterns of cellular migration, interaction, proliferation, and differentiation necessary for robust and efficacious antibody production. Our studies will use histologic, flow cytometric and molecular genetic comparisons of responses to HIV-1 and control vaccines and will identify those differences that may account for the rarity of protective HIV-1 antibody.
The project will identify optimal HIV-1 vaccine candidates by determining which generate efficacious germinal center responses including robust hypermutation and class-switch recombination, clonal proliferation and selection, and establishment of long-lived memory compartments. These studies are fundamental to the rational development of protective HIV-1 vaccines.
|Verkoczy, Laurent; Kelsoe, Garnett; Haynes, Barton F (2014) HIV-1 envelope gp41 broadly neutralizing antibodies: hurdles for vaccine development. PLoS Pathog 10:e1004073|
|Hanson, Melissa C; Bershteyn, Anna; Crespo, Monica P et al. (2014) Antigen delivery by lipid-enveloped PLGA microparticle vaccines mediated by in situ vesicle shedding. Biomacromolecules 15:2475-81|
|Sitkovsky, Michail V; Hatfield, Stephen; Abbott, Robert et al. (2014) Hostile, hypoxia-A2-adenosinergic tumor biology as the next barrier to overcome for tumor immunologists. Cancer Immunol Res 2:598-605|
|Sun, Zhen-Yu J; Cheng, Yuxing; Kim, Mikyung et al. (2014) Disruption of helix-capping residues 671 and 674 reveals a role in HIV-1 entry for a specialized hinge segment of the membrane proximal external region of gp41. J Mol Biol 426:1095-108|
|Liu, Haipeng; Moynihan, Kelly D; Zheng, Yiran et al. (2014) Structure-based programming of lymph-node targeting in molecular vaccines. Nature 507:519-22|
|Holl, T Matt; Yang, Guang; Kuraoka, Masayuki et al. (2014) Enhanced antibody responses to an HIV-1 membrane-proximal external region antigen in mice reconstituted with cultured lymphocytes. J Immunol 192:3269-79|
|Irvine, Darrell J; Swartz, Melody A; Szeto, Gregory L (2013) Engineering synthetic vaccines using cues from natural immunity. Nat Mater 12:978-90|
|Kim, Mikyung; Song, Likai; Moon, James et al. (2013) Immunogenicity of membrane-bound HIV-1 gp41 membrane-proximal external region (MPER) segments is dominated by residue accessibility and modulated by stereochemistry. J Biol Chem 288:31888-901|
|Cain, Derek W; Sanders, Sergio E; Cunningham, Michael M et al. (2013) Disparate adjuvant properties among three formulations of "alum". Vaccine 31:653-60|
|Moon, James J; Suh, Heikyung; Li, Adrienne V et al. (2012) Enhancing humoral responses to a malaria antigen with nanoparticle vaccines that expand Tfh cells and promote germinal center induction. Proc Natl Acad Sci U S A 109:1080-5|
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