Human immunodeficiency virus type-1 (HIV-1) is a retrovirus that infects CD4+ T cells of the immunesystem. If left untreated, HIV-1 infected individuals will progress to AIDS and may ultimately die as a result.Combination antiretroviral therapy is extremely effective at stopping the replication of HIV-1 in infectedindividuals. Despite the success of this therapy at suppressing HIV-1 replication to clinically undetectablelevels, antiretroviral therapy is not curative. This is due to the persistence of HIV-1 in a silent, or latent, statewithin a subset of CD4+ T cells known as resting memory CD4+ T cells. In this latent state, these infected cellsare not targeted by antiretroviral drugs and cannot be eliminated by the immune system. In HIV-1 infectedindividuals, latently infected CD4+ T cells are found at extremely low frequencies (~1 per million restingmemory CD4+ T cells), with the majority found within immune tissues at any given time. This population oflatently infected cells is very stable, demanding that HIV-1 infected individuals remain on antiretroviral therapyindefinitely to avoid rebound of viremia. As such, this population of latently infected CD4+ T cells is the mainbarrier to curing HIV-1 infection. Developing strategies to eliminate latently infected cells is a major focus of the NIH, NIAID, and theHIV-1 research field. To demonstrate the efficacy of therapeutics targeting the latent reservoir, we must beable to measure the frequency of latently infected cells using rapid and accurate assays that can be scaled forwidespread clinical use. Critically, such assays must be capable of accurately measuring the size of the latentreservoir across viral subtypes. Accelevir Diagnostics, LLC has recently developed the IPDA as a novel digitaldroplet PCR assay to measure intact and defective proviruses in a small sample of peripheral blood. The IPDAwas optimized for use in people with subtype B HIV-1 infection, which predominates in the United States andEurope but comprises on a small fraction of people living with HIV-1 worldwide. In this proposal, AccelevirDiagnostics seeks to expand the IPDA coverage to include people living with subtype C HIV-1 infection, whichaccounts for approximately 50% of all people living with HIV-1 worldwide. Broadly, this proposal aims toperform in-depth proviral sequencing to inform expansion of assay coverage followed by assay designadaptation, performance qualification, and analysis of longitudinally collected samples from people living withsubtype C HIV-1 infection. This proposal leverages a close collaboration with the US Military HIV ResearchProgram, enabling access to a unique and cohort of people living with subtype C HIV-1 infection across Africa.
Public Health Relevance Statement: PROJECT NARRATIVE
For HIV-1 infected individuals on suppressive antiretroviral therapy, latent HIV-1 infection of resting
memory CD4+ T cells is the major barrier to a cure. Elimination of these latently infected cells by is being
pursued as a strategy to cure the infection. This proposal details the development and optimization of a new
molecular assay to measure the number of latently infected cells present in individuals with HIV-1 subtype C
infected (roughly 50% of people living with HIV) for use in monitoring the efficacy of HIV-1 cure therapies.
Project Terms: <21+ years old> |