Deep sequencing of the HIV latent reservoir to discern mechanisms of clonal proliferation and HIV persistence

Summary

This project aims to deeply sequence the HIV latent reservoir to characterize provirus clonality and develop models to quantify the contributions of antigen-driven versus homeostatic proliferation to HIV persistence, informing future HIV cure strategies.

What they want

The project involves generating near-full length HIV provirus sequencing datasets to characterize intact and defective provirus clonality distributions in people living with HIV (PLWH) on ART, testing the hypothesis that these distributions mirror uninfected memory CD4+ T cells. It will also generate longitudinal characterizations of in vivo antigen-driven and homeostatic CD4+ T cell proliferation of uninfected CD4s in PLWH on ART using T cell receptor repertoires. This information will then be used to construct mathematical models to estimate the fractional contributions of antigen-driven and homeostatic proliferation to the persistence of the HIV latent reservoir.

Deliverables

Near-full length HIV provirus sequencing datasets deep enough to approximate clonality richness saturation
Characterization of intact and defective provirus clonality distributions in PLWH on ART
Longitudinal characterizations of in vivo antigen-driven and homeostatic CD4+ T cell proliferation of uninfected CD4s in PLWH on ART using T cell receptor repertoires
Mathematical models to estimate the fractional contributions of antigen-driven and homeostatic proliferation to HIV reservoir maintenance
Insights to help design future HIV therapeutic strategies
Predictions for outcomes when HIV cure strategies (e.g., anti-proliferative therapies, personalized therapeutic vaccines) are trialed

Technical requirements

Deep sequencing of HIV latent reservoir
Near-full length HIV provirus sequencing
T cell receptor repertoires analysis
Mathematical modeling