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 an NIAID resource to perform three innovative molecular assays to accurately measure the size of the latent reservoir, the amount of residual viremia present in the peripheral blood, and the transcriptional activity of persistent proviruses. Broadly, this proposal will provide funding to support performance of these assays for the HIV-1 cure research community in a centralized location using standard operating procedures for both laboratory research and clinical trials.
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 establishment of a centralized NIAID resource which will provide qualified assays to accurately quantify latent and expressed HIV reservoirs in research and clinical trials samples from the research community.
