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 #
5UM1AI100645-03
Application #
8681330
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Duke University
Department
Type
DUNS #
City
Durham
State
NC
Country
United States
Zip Code
Pollara, Justin; Easterhoff, David; Fouda, Genevieve G (2017) Lessons learned from human HIV vaccine trials. Curr Opin HIV AIDS 12:216-221
Arakelyan, Anush; Fitzgerald, Wendy; King, Deborah F et al. (2017) Flow virometry analysis of envelope glycoprotein conformations on individual HIV virions. Sci Rep 7:948
Go, Eden P; Ding, Haitao; Zhang, Shijian et al. (2017) Glycosylation Benchmark Profile for HIV-1 Envelope Glycoprotein Production Based on Eleven Env Trimers. J Virol 91:
Verkoczy, Laurent; Alt, Frederick W; Tian, Ming (2017) Human Ig knockin mice to study the development and regulation of HIV-1 broadly neutralizing antibodies. Immunol Rev 275:89-107
Haynes, Barton F; Mascola, John R (2017) The quest for an antibody-based HIV vaccine. Immunol Rev 275:5-10
Bonsignori, Mattia; Liao, Hua-Xin; Gao, Feng et al. (2017) Antibody-virus co-evolution in HIV infection: paths for HIV vaccine development. Immunol Rev 275:145-160
Kelsoe, Garnett; Haynes, Barton F (2017) What Are the Primary Limitations in B-Cell Affinity Maturation, and How Much Affinity Maturation Can We Drive with Vaccination? Breaking through Immunity's Glass Ceiling. Cold Spring Harb Perspect Biol :
Herschhorn, Alon; Sodroski, Joseph (2017) An entry-competent intermediate state of the HIV-1 envelope glycoproteins. Receptors Clin Investig 4:
Ding, Shilei; Verly, Myriam M; Princiotto, Amy et al. (2017) Short Communication: Small-Molecule CD4 Mimetics Sensitize HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity by Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Nonhuman Primates. AIDS Res Hum Retroviruses 33:428-431
Espy, Nicole; Pacheco, Beatriz; Sodroski, Joseph (2017) Adaptation of HIV-1 to cells with low expression of the CCR5 coreceptor. Virology 508:90-107

Showing the most recent 10 out of 220 publications