Using the rhesus macaque (RM) model, we have repeatedly demonstrated that the SIV-specific immune responses elicited by strain 68-1 (Rh157.5/Rh157.4-deleted) RhCMV/SIV vectors (which are characterized by high frequency, broadly distributed, effector-memory CD4+ and CD8+ T cell responses) result in immediate control and ultimate clearance of mucosally-administered, highly pathogenic SIVmac239 virus in 50-60% of vaccinated RM. Although the pattern of the ?arrest and clear? protection observed in these 68-1 RhCMV/SIV vector-vaccinated RM suggests that the early pathogen intercept afforded by the vaccine-elicited ?in place? effector-memory T cells plays a critical role in efficacy, recent data indicates that this unique response characteristic is not, by itself, sufficient for protection. Indeed, we have shown that the CD8+ T cells elicited by the strain 68-1 RhCMV/SIV vectors manifest another very unusual immunologic property: all of these CD8+ T cells were found to recognize epitopes that were restricted by either MHC-II or MHC-E, not conventional MHC- Ia. We further demonstrated that this unconventional epitope targeting was reverted to conventional MHC-Ia restriction by repair of Rh157.5/Rh157.4 expression, which did not otherwise affect the functional or phenotypic characteristics of vector-elicited CD8+ T cells. Remarkably, in 2 independent studies, the Rh157.5/Rh157.4- repaired RhCMV/SIV vectors failed to protect vaccinated RM against SIV challenge, demonstrating that unconventional CD8+ T cell epitope recognition is required for RhCMV/SIV vector efficacy. Recent work has demonstrated that conventional vs. unconventional CD8+ T cell priming is regulated by multiple RhCMV genes, the modification of which effectively programs RhCMV vectors to elicit CD8+ T cell responses with distinct epitope recognition patterns. Based on these data, Projects 2-4 of this program will design and construct RhCMV and HCMV vectors that are strategically modified to both unravel the virologic mechanisms that mediate this CD8+ T cell epitope recognition ?programming?, and to develop vectors that predominantly or exclusively elicit MHC-II- vs. MHC-E-restricted CD8+ T cell responses. Project 1 will be responsible for determining the epitope recognition profile of the CD8+ T cells elicited by each of these modified vectors in RM, and for selecting RhCMV/SIV vectors that differentially elicit MHC-II- vs. MHC-E-restricted CD8+ T cell responses for efficacy testing. Project 1 will then determine the contribution of these response type(s) to efficacy and whether focusing the response on a particular response type improves efficacy, and will also define immunologic correlates of this protection. The insight gained from these studies will be used by Projects 4 and 5 to design, manufacture and clinically test a ?safety- and CD8+ T cell response-optimized? HCMV/HIV vector, and Project 1 will efficacy test the RhCMV/SIV homolog of this clinical vector in RM, using heterologous SIV challenge, to confirm efficacy and immune correlates, as well as determine the kinetics of CMV/SIV vector- mediated protection after vaccination and the dependence of efficacy on boosting and vector dose.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI128741-01
Application #
9239370
Study Section
Special Emphasis Panel (ZAI1-RB-A (S1))
Project Start
Project End
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
1
Fiscal Year
2017
Total Cost
$549,800
Indirect Cost
$191,321
Name
Oregon Health and Science University
Department
Type
Domestic Higher Education
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239