Recent studies have shown that broad neutralizing antibody responses are found in about 20% of HIV-1 infected individuals and develop in most cases during the first two to three years following infecfion. In this program, we seek to study the dynamics and mechanism of development of broad neutralizing antibody responses through access to two large and well-characterized primary infection cohorts, Protocol C (donors from sub-Saharan Africa), and the First Choice Program (donors from Southern California). Our focus in this project will be to characterize the neutralizing specificifies as they emerge and evolve in individuals who develop broad and potent serum neutralizafion.
Our specific aims are:
Aim 1. To map the neutralizing specificities in the sera of individuals with broad and potent neutralizing Ab responses. This characterization will allow the selecfion of the most appropriate donors for isolafion of broadly neutralizing human monoclonal Abs (bNmAbs) in Aim 2 and the design of suitable baits for the isolafion of bNmAbs in collaboration with Project 2. A detailed analysis of the specificities responsible for broad serum neutralization will be carried out on the top 5% of neutralizers in the 2 cohorts.
Aim 2. To isolate and characterize bNmAbs from individuals selected in Aim 1. This informafion will be used to trace the evolutionary history of the broadly neutralizing responses in combination with Project 2. We will use the recently successful high-throughput direct functional screening strategy to isolate bNmAbs from four selected individuals from procedures in Aim 1. We will precisely map the epitopes recognized by the bNmABs. This informafion will be used to design """"""""baits"""""""" to follow the evolufion of the B cell receptor specificity associated with broad neutralization. The studies will yield a panel of new broadly neutralizing antibodies and reveal for the first fime the evolutionary pathway leading to the development of broad neutralizing specificities in interplay with viral escape. The results will have important consequences for vaccine design by showing for example whether high levels of somafic mutations are required for broad neutralization, which would signify the need of immunization strategies favoring prolonged antigen exposure, or whether particular pathways of Ab-Env interacfion and viral escape may favor the development of broad specificities, which will lead to the development of new immunogens and immunizafion protocols.
The field of AIDS vaccine is in great need of immunogens and immunizafion strategies able to efficiently induce broadly neutralizing antibodies. This project will use a novel approach to trace the path by which some individuals develop broadly neutralizing responses and thereby gain knowledge for the design of effective vaccines and vaccine strategies.
|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|
|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|
|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|
|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|
|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|
|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