Deep sequencing of immune receptor rearrangements in lymphocyte populations provides a direct and sensitive tool to characterize and define antibody responses to HIV-1. Despite being found in -20% of chronically infected subjects, it has not yet been possible to induce broadly neutralizing antibodies (BnAbs) by vaccination. Moreover, there is increasing evidence that their expression may be controlled by a variety of immunoregulatory mechanisms and/or their maturation pathways are limited by the number of somatic hypermutations that must accrue. The B Cell Focus Team will isolate the native heavy and light chain antibodies using recombinant antibody technology, and this Antibody Sequencing Scientific Research Support Component will perform 454 deep sequencing to elucidate the full extent of depth and breadth of potentially protective HIV-1 antibody clonal lineages.
Specific Aims Aim 1,To define maturation pathways of BnAb HIV-1 antibodies by performing 454 deep sequencing of immunoglobulin (Ig) variable (V) heavy (H) rearrangements using B cells from HIV-1-infected individuals who are capable of making BnAbs.
Aim 2. To perform 454 deep sequencing of Ig VH rearrangements of B cell repertoires in Env- vaccinated individuals to define maturation pathways of potentially protective HIV-1 antibodies.
Aim 3. To perform 454 deep sequencing of immunoglobulin (Ig) variable (V) heavy (H) rearrangements in HI V-1-infected subjects who do and do not develop BnAbs, and to correlate this information with HIV-1 Env quasispecies complexity in these same individuals;this will allow us to determine to what extent neutralization escape mutations drive BnAb induction.
Development of an HIV-1 vaccine able to induce antibodies active against a broad range of viral variants would be a major breakthrough in combating this disease. The Antibody Sequencing Support Component will use new DNA sequencing methods to thoroughly characterize broadly-neutralizing HlV-1 antibodies that arise in some infected patients, to determine their origin and pathways of development. Paired with sequencing of viruses present in such patients, and structural studies, our data should enable better-informed design of vaccines to stimulate B cells toward generation of broadly-neutralizing antibodies.
|Pardi, Norbert; Hogan, Michael J; Naradikian, Martin S et al. (2018) Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses. J Exp Med 215:1571-1588|
|Eudailey, Joshua A; Dennis, Maria L; Parker, Morgan E et al. (2018) Maternal HIV-1 Env Vaccination for Systemic and Breast Milk Immunity To Prevent Oral SHIV Acquisition in Infant Macaques. mSphere 3:|
|Kelsoe, Garnett; Haynes, Barton F (2018) What Are the Primary Limitations in B-Cell Affinity Maturation, and How Much Affinity Maturation Can We Drive with Vaccination? Breaking through Immunity's Glass Ceiling. Cold Spring Harb Perspect Biol 10:|
|Wagh, Kshitij; Kreider, Edward F; Li, Yingying et al. (2018) Completeness of HIV-1 Envelope Glycan Shield at Transmission Determines Neutralization Breadth. Cell Rep 25:893-908.e7|
|Fu, Qingshan; Shaik, Md Munan; Cai, Yongfei et al. (2018) Structure of the membrane proximal external region of HIV-1 envelope glycoprotein. Proc Natl Acad Sci U S A 115:E8892-E8899|
|Fera, Daniela; Lee, Matthew S; Wiehe, Kevin et al. (2018) HIV envelope V3 region mimic embodies key features of a broadly neutralizing antibody lineage epitope. Nat Commun 9:1111|
|McMichael, Andrew J (2018) Is a Human CD8 T-Cell Vaccine Possible, and if So, What Would It Take? Could a CD8+ T-Cell Vaccine Prevent Persistent HIV Infection? Cold Spring Harb Perspect Biol 10:|
|Williams, Wilton B; Han, Qifeng; Haynes, Barton F (2018) Cross-reactivity of HIV vaccine responses and the microbiome. Curr Opin HIV AIDS 13:9-14|
|Bonsignori, Mattia; Scott, Eric; Wiehe, Kevin et al. (2018) Inference of the HIV-1 VRC01 Antibody Lineage Unmutated Common Ancestor Reveals Alternative Pathways to Overcome a Key Glycan Barrier. Immunity 49:1162-1174.e8|
|Blasi, Maria; Negri, Donatella; LaBranche, Celia et al. (2018) IDLV-HIV-1 Env vaccination in non-human primates induces affinity maturation of antigen-specific memory B cells. Commun Biol 1:134|
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