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.
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