Development of a quantitative assay for intact HIV DNA measures in tissue

Accelevir Diagnostics, Llc, Baltimore MD

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Abstract

Project Summary/Abstract Human immunodeficiency virus type-1 (HIV-1) is a retrovirus that infects CD4+ T cells of the immune system. 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 infected individuals. Despite the success of this therapy at suppressing HIV-1 replication to clinically undetectable levels, antiretroviral therapy is not curative. This is due to the persistence of HIV-1 in a silent, or latent, state within a subset of CD4+ T cells known as resting memory CD4+ T cells. In this latent state, these infected cells are not targeted by antiretroviral drugs and cannot be eliminated by the immune system. In HIV-1 infected individuals, latently infected CD4+ T cells are found at extremely low frequencies (~1 per million resting memory CD4+ T cells), with the majority found within immune tissues at any given time. This population of latently infected cells is very stable, demanding that HIV-1 infected individuals remain on antiretroviral therapy indefinitely to avoid rebound of viremia. As such, this population of latently infected CD4+ T cells is the main barrier to curing HIV-1 infection. Developing strategies to eliminate latently infected cells is a major focus of the NIH, NIAID, and the HIV-1 research field. To demonstrate the efficacy of therapeutics targeting the latent reservoir, we must be able to measure the frequency of latently infected cells using rapid and accurate assays that can be scaled for widespread clinical use in both peripheral blood and immune tissues. Accelevir Diagnostics, LLC is therefore developing a new molecular assay to accurately measure the size of the latent reservoir in immune tissues from HIV-1 infected individuals. Broadly, this proposal aims to develop and optimize our novel assay to measure latent HIV-1 in unfractionated tissues, qualify this assay, define the frequency and dynamics of latent HIV-1 in immune tissue as compared to blood, and demonstrate the potential utility of our assay use previously collected blood and tissue samples from a recently completed HIV-1 eradication trial. !