The development of a successful HIV vaccine will require induction of neutralizing antibodies that can protect from infection by a broad range of HIV isolates. Although antibody responses can be generated as a result of vaccination or infection, these antibodies often recognize only immunodominant, highly variable epitopes that do not confer neutralizing protection. Broadly neutralizing antibodies (BNA) that are capable of neutralizing HIV across clades have been isolated from HIV patients that sustain high CD4 numbers, and low viral titers, over many years. Several of the BNA isolated from this long-term non-progressor (LTNP) population are also reactive to self-antigens, suggesting a relationship with autoreactive B cell development. The B cell source of HIV BNA is unclear but the above observations indicate that these cellular precursors must exist in these patients and should be identifiable. This goal will require fine discrimination of specific B cell subsets and powerful screening technology both of which are available in our laboratory. Accordingly, we propose to identify the cellular source of HIV BNA and determine if autoreactive B cells are enriched for HIV BNA. Discreet B cell subsets expressing validated surface markers will be isolated from healthy patients and those with HIV or Systemic Lupus Erythematosis, expanded, and evaluated for the production of HIV BNA. The results will be important to define the B cell subsets that should be targeted by future vaccines. The information obtained will accordingly inform the design of specific antigen preparations and adjuvant strategies to preferentially stimulate the BNA-producing B cell subsets to become long-lived plasma cells. The development of an effective vaccine to prevent HIV infection will require a better understanding of how to generate antibodies that will neutralize the virus. Similarities may exist between B cells that produce antibodies that prevent HIV infection and those that are found in patients with Lupus. We propose to identify the B cells that produce HIV neutralizing antibodies. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI078459-01
Application #
7460109
Study Section
Special Emphasis Panel (ZAI1-KS-I (J3))
Program Officer
Ferguson, Stacy E
Project Start
2008-05-15
Project End
2010-04-30
Budget Start
2008-05-15
Budget End
2009-04-30
Support Year
1
Fiscal Year
2008
Total Cost
$229,650
Indirect Cost
Name
University of Rochester
Department
Internal Medicine/Medicine
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Kobie, James J; Zheng, Bo; Piepenbrink, Michael S et al. (2015) Functional and Molecular Characteristics of Novel and Conserved Cross-Clade HIV Envelope Specific Human Monoclonal Antibodies. Monoclon Antib Immunodiagn Immunother 34:65-72
Sullivan, Mark A; Brooks, Lauren R; Weidenborner, Philip et al. (2013) Anti-idiotypic monobodies derived from a fibronectin scaffold. Biochemistry 52:1802-13
Alcéna, Danielle C; Kobie, James J; Kaminski, Denise A et al. (2013) 9G4+ antibodies isolated from HIV-infected patients neutralize HIV-1 and have distinct autoreactivity profiles. PLoS One 8:e85098
Kobie, James J; Alcena, Danielle C; Zheng, Bo et al. (2012) 9G4 autoreactivity is increased in HIV-infected patients and correlates with HIV broadly neutralizing serum activity. PLoS One 7:e35356