Project

Development and implementation of a novel genotypic HIV-1 DNA drug resistance test to improve treatment success in people living with HIV

Short Summary

In this project, we will develop, implement, and validate a novel genotypic HIV-1 drug resistance test based on viral DNA rather than RNA as is common practice. The test involves computational methods for distinguishing relevant mutations in the viral DNA that are related to drug resistance from irrelevant hypermutations. These methods will be integrated into V-pipe, a bioinformatics pipeline for automated and reproducible end-to-end analyses of viral next-generation sequencing data. In order to validate the test, we will analyze, in collaboration with the Swiss HIV Cohort Study, a unique data set from over 2000 people living with HIV, which includes HIV-1 DNA sequencing data as well as clinical and epidemiological data.

Goals

First, we aim to develop computational methods for analyzing viral DNA next-generation sequencing data that allow for predicting HIV-1 drug resistance. Viral DNA isolated from PBMCs is heavily hypermutated; hence statistical methods are needed that can separate hypermutations from causal drug resistance mutations. Second, building on our previous work on V-pipe, we aim at creating a computational pipeline that supports fully automated and reproducible end-to-end analyses of viral next-generation sequencing data in a diagnostic setting. Third, we aim to validate DNA-based drug resistance testing on a large dataset from the Swiss HIV Cohort Study comprising data from over 2000 people living with HIV. We will assess the sensitivity of detecting drug resistance mutations and their predictive value for treatment failure.

Significance

This study will be an important step in expanding our diagnostic tools for HIV-1 drug resistance testing, allowing clinicians and people living with HIV to select the optimal antiretroviral therapy. This is particularly important since antiretroviral therapy must be taken for life and virologic failure severely limits treatment options.

Background

The remarkable success of antiretroviral therapy in HIV-infected patients is jeopardized by transmitted or acquired drug resistance. Testing for drug resistance mutations to select optimal personalized drug combinations is routinely performed by sequencing of the viral RNA genomes of plasma viruses. However, there is a second compartment of HIV-1, namely viral DNA in peripheral blood mononuclear cells (PBMCs), particularly relevant for people with low or undetectable plasma viremia. Sequencing viral DNA opens new diagnostic opportunities, but it also comes with new data analysis challenges.