Despite the clinical success of antiretroviral therapy (ART), more people contract human immunodeficiency virus (HIV) infection daily than initiate ART. The difficulties of lifelong ART - particularly in the developing world - make the eradication of HIV imperative. But clearance of a retroviral infection for patients on ART is a herculean task. While much is known about HIV persistence despite ART, many puzzles remain. New tools to address latent infection must replace the paradigms and models used to develop ART. Existing cellular and animal models that represent HIV latency in vivo require further development, and while latent provirus can be purged in the laboratory, a testable, comprehensive therapeutic strategy is not at hand. Therefore we propose the Martin Delaney Collaboratory to Eradicate HIV-1 Infection, a close collaboration of 21 exceptional investigators who have collectively led the field of HIV latency over the last 10 years. To maximize success, we will work across four areas of research to develop the infrastructure and systems needed to define eradication therapies, identify new molecules with therapeutic potential and provide a proof-of-concept for a small molecule based eradication strategy in animal models. Objective 1 will identify the molecular mechanisms underlying viral persistence and latency;Objective 2 will identify drug candidates and therapeutic strategies to reduce the latent viral pool;Objective 3 will establish informative animal model systems to evaluate latency and test therapeutic strategies;and finally. Objective 4 will perform studies in humans to delineate the basis for viral persistence. Three cores will assist research projects with pharmacology, molecular assays, and sequence and expression analysis. An administrative core will assure coordination, and maintain the focus of this experienced and potent group towards translational product development. As a group, we are committed to pooling our resources and expertise to transcend the normal constraints of academic research. Of note, the expertise and durable commitment of Merck Research Laboratories will be critical to delivering therapeutic advances. We are convinced that together we will catalyze advances that will ultimately lead to the eradication of HIV infection.
Despite the success of antiretroviral therapy (ART) in decreasing mortality for HlV-1-infected patients, ART has not cured the disease. A persistent viral reservoir in the T cells of HIV patients receiving potent ART is a significant barrier preventing an HIV cure. Including scientists from eight universities and Merck Research Laboratories, the Martin Delaney Collaboratory will seek to eradicate HIV infection by developing and testing therapies, capable of eventually being tested clinically, that will permanently destroy the viral reservoir. Project 1.1 - Identification Novel Host Factors Regulating HIV Latency Project Leader (PL): Warner Greene (Description as provided by applicant) Quiescent memory CD4 T cells harboring integrated, actively repressed HIV proviruses currently form a formidable barrier to viral eradication. This latent reservoir could be attacked by activating proviral gene expression thereby sensitizing the virus to antiretroviral therapy. For success, this strategy must both prevent viral spread and result in the death of all latently infected cells without producing a toxic state of generalized cellular activation. Currently, no effective therapies for HIV latency exist. We hypothesize that a more complete understanding of the molecular underpinnings of HIV latency - notably, the full range of the host's regulatory factors that promote and antagonize latency - will facilitate the development of effective therapies.
In Aim 1, we will examine five novel candidate HIV repressors identified by genome wide siRNA screening of HIV-infected HeLa cells. These candidates have biological properties consistent with a role in latency and are expressed in lymphoid tissues. Expression of these candidate genes will be analyzed in biologically relevant cells and their function assessed by lentiviral shRNA knockdown.
In Aim 2, we will screen a CD4 T-cell model of HIV latency for microRNAs (miRs) that promotes viral latency by impairing the expression of cellular activators. We will validate miR action using antagomirs in latently infected primary CD4 T-cells.
In Aim 3, we will use bioinformatic and transcriptional profiling approaches to identify the host gene products that are suppressed by these miRs. Using this dual experimental approach, we will identify cellular factors that naturally promote and antagonize HIV latency. Where appropriate, mechanism-of-action studies will be performed. Identified targets will be prioritized, based on the robustness of their activity and overall """"""""drugability,"""""""" for entry into small-molecule high-throughput screening assays and primary and secondary screening assays will be developed. These proposed studies could identify small molecules that either inhibit the most interesting cellular repressors or activate the most compelling mRNA-regulated HIV activators. These studies fully support the goal of the Collaboratory - to identify combinations of nontoxic small molecules that can eradicate the virus or produce a functional cure (drug-free remission).
These studies promise to deepen our understanding of the cellular factors that both promote and antagonize HIV latency and ultimately to provide new approaches for purging HIV from the latent reservoir. Ultimately, we seek to translate these basic insights into HIV latency into combinations of small molecule inducers that effectively purge the latent reservoir. Success in these studies could radically change the landscape of clinical care for HIV-infected patients throughout the world.
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