Most of our understanding regarding the cellular reservoirs that maintain viral persistence has been derived from studies with lymphocytes. In contrast, the role played by myeloid-lineage cells (e.g., monocyte/macrophage and dendritic cells) in viral replication and persistence is not well understood. Our ongoing studies indicate that primate lentiviruses have evolved functions that specifically allow them to establish persistent reservoirs within myeloid-lineage cells. As the field now explores strategies that attempt to eradicate the virus from infected individuals, an understanding of the role played by myeloid-lineage cells in viral replication and persistence is essential. In this Project, we propose experiments that will define the role for macrophages in viral persistence and that will explore a strategy for removal of this potential viral reservoir in vivo. Our broadly-defined objectives are to define the mechanisms whereby HIV persists in macrophages (focusing on an HIV-induced survival pathway mediated by monocyte colony stimulating factor, or MCSF) and to define with precision the geospatial distribution of latently-infected cells in optimally treated hosts.
In Aim 1, we will determine the molecular mechanisms of macrophage latency as well as a strategy to interrupt this mechanism. We will also characterize the impact of MCSF and MCSF antagonists on chronic/latent infection of macrophage in vitro. This information will guide a strategy to purge infected macrophage in vivo (Aim 3 and Project 1).
In Aim 2, we will determine whether macrophages maintain viral persistence in the face of antiretroviral suppression. More specifically, we will characterize the viral genomes in tissue macrophages isolated from lymph node and gut-associated lymphoid tissue of patients on suppressive ART (with Project 6) and we will exploit the non-human primate model to extend our sampling of tissue macrophages into compartments not readily accessible in HIV-infected patients (with Project 1). Finally, in Aim 3, we will test strategies to purge infected macrophage in non-human primates. In direct association with analogous studies carried out in Project 1, we will examine whether MCSF antagonism eradicates SIV from the macrophage reservoir of the non-human primate.

Public Health Relevance

To attain the goal of viral eradication, an understanding of the reservoirs that allow HIV to persist in the face of therapy is essential. We hypothesize that, during suppressive ART, HIV establishes latent/chronic infection of T-cells and myeloid cells (especially macrophages) and that these reservoirs are a barrier to viral eradication. We will establish a role for myeloid cells in viral persistence during ART and develop a strategy to purge myeloid cell reservoirs.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1)
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University of California San Francisco
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Okoye, Afam A; Hansen, Scott G; Vaidya, Mukta et al. (2018) Early antiretroviral therapy limits SIV reservoir establishment to delay or prevent post-treatment viral rebound. Nat Med 24:1430-1440
Winckelmann, Anni; Morcilla, Vincent; Shao, Wei et al. (2018) Genetic characterization of the HIV-1 reservoir after Vacc-4x and romidepsin therapy in HIV-1-infected individuals. AIDS 32:1793-1802
Wykes, Michelle N; Lewin, Sharon R (2018) Immune checkpoint blockade in infectious diseases. Nat Rev Immunol 18:91-104
Lee, Sulggi A; Elliott, Julian H; McMahon, James et al. (2018) Population Pharmacokinetics and Pharmacodynamics of Disulfiram on Inducing Latent HIV-1 Transcription in a Phase IIb Trial. Clin Pharmacol Ther :
Kumar, Nitasha A; van der Sluis, Renee M; Mota, Talia et al. (2018) Myeloid Dendritic Cells Induce HIV Latency in Proliferating CD4+ T Cells. J Immunol 201:1468-1477
Walters, Lucy C; Harlos, Karl; Brackenridge, Simon et al. (2018) Pathogen-derived HLA-E bound epitopes reveal broad primary anchor pocket tolerability and conformationally malleable peptide binding. Nat Commun 9:3137
Adland, Emily; Hill, Matilda; Lavandier, Nora et al. (2018) Differential Immunodominance Hierarchy of CD8+ T-Cell Responses in HLA-B*27:05- and -B*27:02-Mediated Control of HIV-1 Infection. J Virol 92:
Boyer, Zoe; Palmer, Sarah (2018) Targeting Immune Checkpoint Molecules to Eliminate Latent HIV. Front Immunol 9:2339
Wang, Chia-Ching; Thanh, Cassandra; Gibson, Erica A et al. (2018) Transient loss of detectable HIV-1 RNA following brentuximab vedotin anti-CD30 therapy for Hodgkin lymphoma. Blood Adv 2:3479-3482
Reeves, Daniel B; Duke, Elizabeth R; Wagner, Thor A et al. (2018) A majority of HIV persistence during antiretroviral therapy is due to infected cell proliferation. Nat Commun 9:4811

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