The Genomics Scientific Support Component of CHAVI ID will focus its efforts on understanding the genetic contributions to immunological phenotypes relevant to responses to HIV-1 vaccination, with particular, but not sole, emphasis on the genetics of induction of broad neutralizing antibodies. In support of this work, we will also establish the core areas of competency that will be required for the SRSC to study the genetic and genomic bases and correlates of phenotypes of interest in HVTN and MHRP vaccine trials.
Specific Aims Aim 1: To use whole genome sequencing to identify genetic correlates of HlV-1 infected patients who do and do not make broadly neutralizing antibodies during chronic infection. To achieve this aim we will perform whole genome sequencing on 50 broad neutralizing subjects, who exhibit the greatest breadth of neutralizing antibodies as determined by the B Cell Focus group and the Neutralizing Antibody SRSC. Variants of nterest identified in these patients will be followed up in a larger cohort of approximately 600 chronically infected patients who have been characterized for degree of plasma neutralizing activity.
Aim 2 : To relate host gene variation to restricted VH gene usage and other characteristics of the immunoglobulin repertoire as characterized by deep sequencing of the variable heavy (VH) VDJ region.
Aim 3 : To use RNA sequencing (RNA-Seq) to characterize the transcriptomes of HIV responsive CD4 positive T cells and Tfh cells in vaccinated rhesus monkeys and humans and to relate transcriptomes of helper CD4 cells to qualitative features of antibody responses to vaccination. To achieve this aim we will build upon our existing experience with RNA-Seq to establish a RNA sequence analysis pipeline that is comparable to our whole genome and exome sequence analysis pipeline.
Aim 4 : To use whole genome sequencing to study genetic bases of key aspects of the immune responses to vaccination observed in the RV144 trial.
The work proposed by the Genomics SRSC of CHAVI ID will provide new insights into the genetic contributions of immunological phenotypes relevant to responses to an HIV vaccination. These insights may help to identify genetic characteristics that regulate vaccine responses and aid in design of vaccines and in evaluation of vaccine trial results.
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