Abstract

Little is known about the cellular mechanisms involved in generating HIV bnAbs. BnAbs are very difficult to develop and have traits indicative of extensive affinity maturation in germinal centers (GC). One hypothesis is that Tfh cells in the GC are important for driving the development of HIV bnAbs. Follicular helper T cells (Tfh) are the specialized CD4 T cells for B cell help and are necessary and limiting for GCs. (1) How do Tfh cells enhance HIV bnAb development? Is it related to Tfh quantities and/or selective functions? (2) How is somatic hypermutation related to the likelihood of bnAb development? GC SHM activity is necessary for bnAb development, but is there a quantitative relationship? (3) What B cell characteristics are critical to bnAb development? We hypothesize that bnAb development in HIV+ patients may be primarily dependent on (A) unusual B cell repertoire features, such as glycan reactivity; (B) a particular category of B cell response; and/or (C) overall sequence space explored by SHM.

Public Health Relevance

A broadly neutralizing antibody- (bnAb-) directed HIV vaccine is possible, in concept, but exceptional immunological hurdles must be overcome to reach that goal. A successful bnAb-directed HIV vaccine would be a far more sophisticated immunological accomplishment than any currently licensed vaccine. Our projects aim to discover and understand critical aspects of T and B cells immunology of the pathways of bnAb development in humans, using blood samples from a large longitudinal cohort of HIV+ individuals.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI124796-02
Application #
9303875
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Singh, Anjali
Project Start
2016-06-24
Project End
2021-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
2
Fiscal Year
2017
Total Cost
$450,000
Indirect Cost
$200,000

  Institution

Name
La Jolla Institute
Department
Type
Research Institutes
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037

  Publications

Havenar-Daughton, Colin; Abbott, Robert K; Schief, William R et al. (2018) When designing vaccines, consider the starting material: the human B cell repertoire. Curr Opin Immunol 53:209-216
Abbott, Robert K; Lee, Jeong Hyun; Menis, Sergey et al. (2018) Precursor Frequency and Affinity Determine B Cell Competitive Fitness in Germinal Centers, Tested with Germline-Targeting HIV Vaccine Immunogens. Immunity 48:133-146.e6
Reiss, Samantha; Baxter, Amy E; Cirelli, Kimberly M et al. (2017) Comparative analysis of activation induced marker (AIM) assays for sensitive identification of antigen-specific CD4 T cells. PLoS One 12:e0186998