The induction of both CD4+ and CD8+ T cell responses will be of central importance for vaccine protection against HIV-1. However, a number of major questions must be answered before a vaccine can be developed that optimizes these immune responses. While we know that an optimal vaccine-induced antibody response will require CD4+ T cell help, the nature of the help that will potentiate the highest titer and most durable antibody response remains unclear. Although CD8+ T cells have been shown to contribute to containment of HIV-1 replication, the effectiveness of this anti-viral response is limited by the extreme sequence variability of circulating HIV-1 strains and the propensity of the virus to mutate away from recognition by these effector cells. Truly effective CD8+ T cell containment of HIV-1 replication can only occur if T cell responses are generated through vaccination that can pre-empt the ability of the virus to escape from cellular immune recognition. The studies described in this focus address these central issues in HIV-1 vaccine development.
Specific Aims are as follows.
Aim 1. Evaluate different priming vectors for their ability to stimulate CD4+ Th2 cells and T follicular helper (Tfh) cells in macaques.
Aim 2. Characterize CD4+ Th2 cell and Tfh cell responses elicited by HIV-1 vaccines in humans Aim 3. Determine impact of naive repertoires on post-vaccination response of HIV-1 Env-specific CD4+T cells in humans.
Aim 4. Compare mosaic and conserved region vaccines for their induction of CD8+ T cell responses.
Aim 5. Apply new understanding of immunodominance to improve vaccine-elicited CD8+ T cell responses. The information gained in addressing these aims will lead directly to the design of the next generation of vaccines that will stimulate more protective CD4+ T cell and CD8+ T cell responses.

Public Health Relevance

An effective HIV vaccine will have to stimulate long lasting antibody response and cellular (T cell) immune responses. Two types of T cells are important, CD4+ T cells that help B cells to generated effective antibody and CD8+ T cells that act directly on virus infected cells. This focus will find new ways to generate both.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project with Complex Structure Cooperative Agreement (UM1)
Project #
5UM1AI100645-02
Application #
8508868
Study Section
Special Emphasis Panel (ZAI1-JBS-A)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$324,000
Indirect Cost
Name
Duke University
Department
Type
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Chen, Shuobing; Wu, Jiayi; Lu, Ying et al. (2016) Structural basis for dynamic regulation of the human 26S proteasome. Proc Natl Acad Sci U S A 113:12991-12996
Tian, Ming; Cheng, Cheng; Chen, Xuejun et al. (2016) Induction of HIV Neutralizing Antibody Lineages in Mice with Diverse Precursor Repertoires. Cell 166:1471-1484.e18
Love, Tanzy M T; Park, Sung Yong; Giorgi, Elena E et al. (2016) SPMM: estimating infection duration of multivariant HIV-1 infections. Bioinformatics 32:1308-15
Barton, John P; Goonetilleke, Nilu; Butler, Thomas C et al. (2016) Relative rate and location of intra-host HIV evolution to evade cellular immunity are predictable. Nat Commun 7:11660
Astronomo, Rena D; Santra, Sampa; Ballweber-Fleming, Lamar et al. (2016) Neutralization Takes Precedence Over IgG or IgA Isotype-related Functions in Mucosal HIV-1 Antibody-mediated Protection. EBioMedicine 14:97-111
Herschhorn, Alon; Ma, Xiaochu; Gu, Christopher et al. (2016) Release of gp120 Restraints Leads to an Entry-Competent Intermediate State of the HIV-1 Envelope Glycoproteins. MBio 7:
Theiler, James; Yoon, Hyejin; Yusim, Karina et al. (2016) Epigraph: A Vaccine Design Tool Applied to an HIV Therapeutic Vaccine and a Pan-Filovirus Vaccine. Sci Rep 6:33987
Ding, Shilei; Tolbert, William D; Prévost, Jérémie et al. (2016) A Highly Conserved gp120 Inner Domain Residue Modulates Env Conformation and Trimer Stability. J Virol 90:8395-409
Jeffries Jr, T L; Sacha, C R; Pollara, J et al. (2016) The function and affinity maturation of HIV-1 gp120-specific monoclonal antibodies derived from colostral B cells. Mucosal Immunol 9:414-27
Abdul-Jawad, Sultan; Ondondo, Beatrice; van Hateren, Andy et al. (2016) Increased Valency of Conserved-mosaic Vaccines Enhances the Breadth and Depth of Epitope Recognition. Mol Ther 24:375-84

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