In many patients with HIV-1 infection, highly active antiretroviral therapy (HAART) successfully suppresses viral loads and restores CD4+ T cell numbers. However, a major latent reservoir identified in resting CD4+ T cells poses a great barrier to eradication and ensures viral persistence in patients. The understanding of how such a latent reservoir is formed is quite limited. A more complete understanding of the mechanisms contributing to the establishment of the reservoir will influence the strategies in battling viral persistence. Some recent studies done in vivo or ex vivo suggested that the microenvironment of the lymphoid tissue and cell-cell interactions in vivo played important roles in latency formation in resting CD4+ T cells. Moreover, endothelial cells, which physiologically interact readily with T cells in the lymphoid tissues in vivo, were shown to induce both productive and latent HIV infection in resting CD4+ T cells and might play a significant role in latency formation in these cells in vivo. The importance of endothelial cells in HIV infection and latency formation in resting CD4+ T cells was established in the last funding period, and the overall goal of this study is to characterize the interactions of endothelial cells with resting CD4+ T cells in the context of HIV-1 infection and latency.
The specific aims are: 1. To examine the effect of IL6, which is secreted by endothelial cells, in HIV infection of resting CD4+ T cells. 2. To compare the effect of lymphatic EC with HUVEC on HIV infection of resting CD4+ T cells. 3. To identify potential cellular changes involved in allowing HIV infection of resting CD4+ T cells stimulated by IL6 and endothelial cells. The knowledge gained from this study will significantly improve the understanding of HIV latent reservoir formation and will influence the strategies in battling viral persistence. It will also provide insight into the mechanisms contributing to HIV infection of CD4+ T cells and may contribute to potential innovative intervention.
The biggest barrier to the eradication of HIV-1 diseases is the latent viral reservoir in resting CD4+ T cells. The proposed study aims to characterize the interactions between endothelial cells and resting CD4+ T cells in the context of HIV-1 infection and latency formation. An answer to this question will increase our understanding of HIV infection and persistence and contribute to potential innovative intervention in treating HIV diseases.
| Schilthuis, Meghan; Verkaik, Seth; Walhof, Mackenzie et al. (2018) Lymphatic endothelial cells promote productive and latent HIV infection in resting CD4+ T cells. Virol J 15:152 |
| Morris 3rd, John Henry; Nguyen, Tran; Nwadike, Abuoma et al. (2017) Soluble Factors Secreted by Endothelial Cells Allow for Productive and Latent HIV-1 Infection in Resting CD4+ T Cells. AIDS Res Hum Retroviruses 33:110-120 |
| Shen, Anding; Baker, Jacob J; Scott, Geoffrey L et al. (2013) Endothelial cell stimulation overcomes restriction and promotes productive and latent HIV-1 infection of resting CD4+ T cells. J Virol 87:9768-79 |
