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.
|DelagrÃ¨verie, HÃ©loÃ¯se M; Delaugerre, Constance; Lewin, Sharon R et al. (2016) Ongoing Clinical Trials of Human Immunodeficiency Virus Latency-Reversing and Immunomodulatory Agents. Open Forum Infect Dis 3:ofw189|
|Hansen, Erik C; Ransom, Monica; Hesselberth, Jay R et al. (2016) Diverse fates of uracilated HIV-1 DNA during infection of myeloid lineage cells. Elife 5:|
|Barton, Kirston; Hiener, Bonnie; Winckelmann, Anni et al. (2016) Broad activation of latent HIV-1 in vivo. Nat Commun 7:12731|
|Murray, Alexandra J; Kwon, Kyungyoon J; Farber, Donna L et al. (2016) The Latent Reservoir for HIV-1: How Immunologic Memory and Clonal Expansion Contribute to HIV-1 Persistence. J Immunol 197:407-17|
|Crowell, Trevor A; Fletcher, James Lk; Sereti, Irini et al. (2016) Initiation of antiretroviral therapy before detection of colonic infiltration by HIV reduces viral reservoirs, inflammation and immune activation. J Int AIDS Soc 19:21163|
|Yong, Yean K; Shankar, Esaki M; Solomon, Ajantha et al. (2016) Polymorphisms in the CD14 and TLR4 genes independently predict CD4+ T-cell recovery in HIV-infected individuals on antiretroviral therapy. AIDS 30:2159-68|
|Siliciano, Janet D; Siliciano, Robert F (2016) Recent developments in the effort to cure HIV infection: going beyond N = 1. J Clin Invest 126:409-14|
|Phillips, Andrew N; Cambiano, Valentina; Revill, Paul et al. (2016) Identifying Key Drivers of the Impact of an HIV Cure Intervention in Sub-Saharan Africa. J Infect Dis 214:73-9|
|Sattentau, Quentin J; Stevenson, Mario (2016) Macrophages and HIV-1: An Unhealthy Constellation. Cell Host Microbe 19:304-10|
|Massanella, Marta; Fromentin, RÃ©mi; Chomont, Nicolas (2016) Residual inflammation and viral reservoirs: alliance against an HIV cure. Curr Opin HIV AIDS 11:234-41|
Showing the most recent 10 out of 133 publications