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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project with Complex Structure Cooperative Agreement (UM1)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-JBS-A (M1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Duke University
United States
Zip Code
Pollara, Justin; Easterhoff, David; Fouda, Genevieve G (2017) Lessons learned from human HIV vaccine trials. Curr Opin HIV AIDS 12:216-221
Arakelyan, Anush; Fitzgerald, Wendy; King, Deborah F et al. (2017) Flow virometry analysis of envelope glycoprotein conformations on individual HIV virions. Sci Rep 7:948
Go, Eden P; Ding, Haitao; Zhang, Shijian et al. (2017) Glycosylation Benchmark Profile for HIV-1 Envelope Glycoprotein Production Based on Eleven Env Trimers. J Virol 91:
Verkoczy, Laurent; Alt, Frederick W; Tian, Ming (2017) Human Ig knockin mice to study the development and regulation of HIV-1 broadly neutralizing antibodies. Immunol Rev 275:89-107
Haynes, Barton F; Mascola, John R (2017) The quest for an antibody-based HIV vaccine. Immunol Rev 275:5-10
Bonsignori, Mattia; Liao, Hua-Xin; Gao, Feng et al. (2017) Antibody-virus co-evolution in HIV infection: paths for HIV vaccine development. Immunol Rev 275:145-160
Kelsoe, Garnett; Haynes, Barton F (2017) 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 :
Herschhorn, Alon; Sodroski, Joseph (2017) An entry-competent intermediate state of the HIV-1 envelope glycoproteins. Receptors Clin Investig 4:
Ding, Shilei; Verly, Myriam M; Princiotto, Amy et al. (2017) Short Communication: Small-Molecule CD4 Mimetics Sensitize HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity by Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Nonhuman Primates. AIDS Res Hum Retroviruses 33:428-431
Espy, Nicole; Pacheco, Beatriz; Sodroski, Joseph (2017) Adaptation of HIV-1 to cells with low expression of the CCR5 coreceptor. Virology 508:90-107

Showing the most recent 10 out of 220 publications