Current antiretroviral combination therapy is extremely effective at suppressing HIV-1 viremia below to the limit of detection of standard clinical assays, however it is unable to fully eradicate HIV-1. As a consequence, once treatment is stopped, HIV-1 replication can rapidly rebound from the latent reservoir, and typically reaches pre-treatment levels of HIV-1 replication within a short period of time. Thus, the understanding of mechanisms contributing to HIV-1 persistence despite ART, and the development of therapeutic strategies that target persistent virus, represent one of the highest priorities in current HIV-1 research. In this application, we hypothesize that in samples from long- term treated individuals, infected long-lived CD4 T cells will preferentially express HIV RNA-TAR, which will confer to the cells a survival advantage. Thus, here we propose to deeply characterize single cells exclusively expressing HIV RNA-TAR in CD4 T subsets from ART-treated patients. In addition, HIV integration sites sequencing will be used to determine the long-term persistence and the clonal expansion capabilities of cells expressing HIV RNA-TAR during prolonged ART. If successful, these investigations may lead to the identification of the exclusive signatures of latently infected cells in vivo, re-directing current efforts in design clinical straegies aimed at cure HIV, thus addressing one of the highest-priority issues in current HIV-1 research.
Identifying the mechanisms by which HIV is able to persist for prolonged periods of time in patients under antiretroviral therapy is crucial for the development of new strategies targeting the latent reservoir. In here, we propose to deeply characterize resting CD4 T cells from ART-treated patients expressing the TAR RNA element in a effort to identify exclusive signatures of latently infected cells in vivo.
