Development of an effective HIV-1 vaccine remains an unmet goal. Success in this endeavor will require a better understanding of how HIV-1 engages the adaptive immune system, including CD4+ T cells (TCD4+) that are instrumental in the development of effective humoral and cellular immunity. TCD4+ are activated by antigen-derived peptides complexed with Major Histocompatibility Complex class II molecules (MHC-II). According to convention, these peptides are derived from extracellular antigen that is degraded and loaded onto nascent MHC- II in the endosomal compartment of an antigen presenting cell (APC). However, our work with influenza and ectromelia viruses indicates that peptide generation is far more complex, with several fundamentally distinct antigen processing modes in play. Division of labor between these modes is governed by parameters such as physical properties of the virion and replication strategy, which is unique to each virus. How this division plays out for HIV-1 is unknown, since surprisingly little work has been done in this area despite the potential for major impact on rational vaccine design. Here we propose to elucidate the MHC-II processing landscape for HIV-1, and initiate investigation of the underlying processing machinery. This R21 funding mechanism will serve as a springboard for continued mechanistic studies in one direction, and the application of emerging concepts to rational vaccine design in the other.

Public Health Relevance

CD4+ T cells (TCD4+) play critical roles in the defense against viral infections, but little is known about how this occurs in the case of HIV-1. This project aims to understand how TCD4+ sense HIV-1 infection with the goal of using this information to engineer a more effective vaccine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI141110-02
Application #
9762836
Study Section
HIV/AIDS Vaccines Study Section (VACC)
Program Officer
Mcdonald, David Joseph
Project Start
2018-08-15
Project End
2020-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19146