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.
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.
|Stevenson, Mario (2015) Role of myeloid cells in HIV-1-host interplay. J Neurovirol 21:242-8|
|Dunham, Richard M; Vujkovic-Cvijin, Ivan; Yukl, Steven A et al. (2014) Discordance between peripheral and colonic markers of inflammation during suppressive ART. J Acquir Immune Defic Syndr 65:133-41|
|Ribeiro, Susan P; Milush, Jeffrey M; Cunha-Neto, Edecio et al. (2014) The CD8? memory stem T cell (T(SCM)) subset is associated with improved prognosis in chronic HIV-1 infection. J Virol 88:13836-44|
|Stock, P G; Barin, B; Hatano, H et al. (2014) Reduction of HIV persistence following transplantation in HIV-infected kidney transplant recipients. Am J Transplant 14:1136-41|
|Bullen, C Korin; Laird, Gregory M; Durand, Christine M et al. (2014) New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo. Nat Med 20:425-9|
|Dahl, Viktor; Peterson, Julia; Fuchs, Dietmar et al. (2014) Low levels of HIV-1 RNA detected in the cerebrospinal fluid after up to 10 years of suppressive therapy are associated with local immune activation. AIDS 28:2251-8|
|Gray, Lachlan R; Roche, Michael; Flynn, Jacqueline K et al. (2014) Is the central nervous system a reservoir of HIV-1? Curr Opin HIV AIDS 9:552-8|
|Kim, Michelle; Hosmane, Nina N; Bullen, C Korin et al. (2014) A primary CD4(+) T cell model of HIV-1 latency established after activation through the T cell receptor and subsequent return to quiescence. Nat Protoc 9:2755-70|
|Cockerham, Leslie R; Jain, Vivek; Sinclair, Elizabeth et al. (2014) Programmed death-1 expression on CD4? and CD8? T cells in treated and untreated HIV disease. AIDS 28:1749-58|
|Anderson, Jenny L; Cheong, Karey; Lee, Amas K H et al. (2014) Entry of HIV in primary human resting CD4(+) T cells pretreated with the chemokine CCL19. AIDS Res Hum Retroviruses 30:207-8|
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