Although neutralizing antibodies are likely to be required for an effective AIDS vaccine, to date no candidate vaccine has been found to elicit broad neutralizing responses. A significant fraction of HIV-1-infected individuals eventually develop potent and broad neutralizing antibody responses, typically within 2 to 3 years following infection. The over-arching goal of this Program is to undertake a comprehensive, multidisciplinary effort to define correlates and mechanisms of the development of broadly neutralizing antibody responses. We have assembled an accomplished team of investigators with different fields of expertise and have secured access to two large and well-characterized longitudinal cohorts of primary infection: lAVI Protocol C in sub-Sahara Africa and UCSD First Choice in Southern California that will together provide over 500 eligible participants to be used for the stated goals of the program. We will use a variety of complementary approaches to address fundamental questions concerning the development of broadly neutralizing responses. These questions include: - what are the clinical correlates of the development of broad neutralizing antibody (bNAb) responses? - does the nature of the founder virus influence the development of bNAb responses? - do broad and potent neutralizing responses protect against HIV-1 superinfection? - What are the neutralizing antibody specificities in sera from individuals with broad neutralizing activity? - What is the evolutionary history of bNAb responses? - are there specific viral motifs associated with the development of bNAb responses? - does B cell dysfunction during HIV-infection prevent the development of broad responses? - How do CD4+ T cell helper responses influence the development of the bNAb responses? Answers to these questions will shed light on how and why neutralization breadth develops in some individuals and may reveal efficient vaccine strategies.

Public Health Relevance

Broadly neutralizing antibodies, believed to be a crucial component of an AIDS vaccine, have not been induced by current vaccine candidates but are generated naturally by a subset of HIV infected individuals. In a multidisciplinary approach, we propose to study how these antibodies arise in natural infection so that we can apply lessons learned to the design of effective HIV vaccines and vaccine strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI090970-03
Application #
8310205
Study Section
Special Emphasis Panel (ZAI1-PTM-A (M4))
Program Officer
Malaspina, Angela
Project Start
2010-09-01
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2012
Total Cost
$2,452,497
Indirect Cost
$342,949
Name
International AIDS Vaccine Initiative
Department
Type
DUNS #
020790895
City
New York
State
NY
Country
United States
Zip Code
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
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
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
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
Doores, Katie J; Kong, Leopold; Krumm, Stefanie A et al. (2015) Two classes of broadly neutralizing antibodies within a single lineage directed to the high-mannose patch of HIV envelope. J Virol 89:1105-18
Shah, Kartik A; Clark, John J; Goods, Brittany A et al. (2015) Automated pipeline for rapid production and screening of HIV-specific monoclonal antibodies using pichia pastoris. Biotechnol Bioeng 112:2624-9
Frost, Simon D W; Murrell, Ben; Hossain, A S Md Mukarram et al. (2015) Assigning and visualizing germline genes in antibody repertoires. Philos Trans R Soc Lond B Biol Sci 370:
Murrell, Ben; Weaver, Steven; Smith, Martin D et al. (2015) Gene-wide identification of episodic selection. Mol Biol Evol 32:1365-71
Ozkumur, Ayca Yalcin; Goods, Brittany A; Love, J Christopher (2015) Development of a High-Throughput Functional Screen Using Nanowell-Assisted Cell Patterning. Small 11:4643-50

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