Most individuals with chronic HIV infection experience massive dysregulation of the immune system. Longlived memory B cells disappear, while immature B cells are hyperactivated and produce significant quantities of ineffective immunoglobulin. Furthermore, CD4 cells, the primary targets of HIV, steadily decline during the chronic phase of infection. Approximately 10-20% of HIV infected individuals overcome or escape this widespread immune dysfunction and produce broadly neutralizing antibodies to HIV. An understanding of how these indivduals generate broadly neutralizing antibodies to HIV is critical for HIV vaccine development. We hypothesize that H1V+ elite neutralizers have a less disrupted B lymphocyte compartment and/or an enhanced population of follicular helper CD4 T lymphocytes when compared to average or poorly neutralizing individuals. This hypothesis will be tested by multiparameter flow cytometric analysis of B and T lymphocyte populations at two early and two late time points post-infection, comparing indivuals who generate broadly neutralizing antibodies with average/poor neutralizers and uninfected individuals. The ability of B lymphocytes to differentiate into antibody secreting cells and the capacity of follicular T helper CD4 cells to produce important helper cytokines, such as IL-4 and IL-21, will also be compared in elite and poorly neutralizing individuals. These findings will help determine how elite neutralizers generate useful antibodies to HIV, and could greatly assist in the development of an effective HIV vaccine.

Public Health Relevance

A small percentage of HIV+ individuals generate broadly neutralizing antibodies to viral coat proteins. Understanding how the immune response in this subset of patients differs from the majority of HIV infected people is crucial for HIV vaccine development and therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI090970-04
Application #
8526362
Study Section
Special Emphasis Panel (ZAI1-PTM-A)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2013
Total Cost
$274,355
Indirect Cost
$68,143
Name
International AIDS Vaccine Initiative
Department
Type
DUNS #
020790895
City
New York
State
NY
Country
United States
Zip Code
Wagner, Gabriel A; Landais, Elise; Caballero, Gemma et al. (2017) Intrasubtype B HIV-1 Superinfection Correlates with Delayed Neutralizing Antibody Response. J Virol 91:
Landais, Elise; Murrell, Ben; Briney, Bryan et al. (2017) HIV Envelope Glycoform Heterogeneity and Localized Diversity Govern the Initiation and Maturation of a V2 Apex Broadly Neutralizing Antibody Lineage. Immunity 47:990-1003.e9
Landais, Elise; Huang, Xiayu; Havenar-Daughton, Colin et al. (2016) Broadly Neutralizing Antibody Responses in a Large Longitudinal Sub-Saharan HIV Primary Infection Cohort. PLoS Pathog 12:e1005369
Var, Susanna R; Day, Tyler R C; Vitomirov, Andrej et al. (2016) Mitochondrial injury and cognitive function in HIV infection and methamphetamine use. AIDS 30:839-48
Karris, Maile Y; Umlauf, Anya; Vaida, Florin et al. (2016) A randomized controlled clinical trial on the impact of CCR5 blockade with maraviroc in early infection on T-cell dynamics. Medicine (Baltimore) 95:e5315
MacLeod, Daniel T; Choi, Nancy M; Briney, Bryan et al. (2016) Early Antibody Lineage Diversification and Independent Limb Maturation Lead to Broad HIV-1 Neutralization Targeting the Env High-Mannose Patch. Immunity 44:1215-26
Krumm, Stefanie A; Mohammed, Hajer; Le, Khoa M et al. (2016) Mechanisms of escape from the PGT128 family of anti-HIV broadly neutralizing antibodies. Retrovirology 13:8
Wertheim, Joel O; Murrell, Ben; Smith, Martin D et al. (2015) RELAX: detecting relaxed selection in a phylogenetic framework. Mol Biol Evol 32:820-32
Smith, Martin D; Wertheim, Joel O; Weaver, Steven et al. (2015) Less is more: an adaptive branch-site random effects model for efficient detection of episodic diversifying selection. Mol Biol Evol 32:1342-53
Martin, Darren P; Murrell, Ben; Golden, Michael et al. (2015) RDP4: Detection and analysis of recombination patterns in virus genomes. Virus Evol 1:vev003

Showing the most recent 10 out of 42 publications