In most patients with HIV-1 infection, antiretroviral therapy (ART) successfully suppresses viral loads and restores CD4+ T cell numbers. However, lifelong therapy is required to maintain viral suppression, primarily due to a major latent reservoir in resting CD4+ T cells. The latent reservoir poses a great barrier to HIV cure and ensures viral persistence in patients. Knowledge about 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 impact the strategies in battling viral persistence. Microenvironment of the lymphoid tissue and cell-cell interactions in vivo played important roles in latency formation in resting CD4+ T cells. It was found that endothelial cells, which physiologically interact readily with T cells in the lymphoid tissues in vivo, promote both productive and latent HIV infection in resting CD4+ T cells and may play a significant role in latency formation in these cells in vivo. Having established the importance of endothelial cells (EC) in HIV infection and latency formation, this study is to further elucidate the effects of different types of endothelial cells as well as virus types on resting and activated T cells in HIV infection and latency formation, as well as exploring mechanisms involved in interactions between endothelial cells and CD4+ T cells.
The specific aims of the proposal are: 1. To investigate the effect of intestinal EC on HIV infection of resting and activated CD4+ T cells. 2. To identify potential cellular factors and additional cytokines involved in EC stimulation of resting CD4+ T cells. 3. To compare infection of R5-tropic virus with X4-tropic virus in infection of EC stimulated resting and activated CD4+ T 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 HIV-1 cure is the latent viral reservoir in CD4+ T cells. The proposed study aims to characterize the contributions of endothelial cells to HIV-1 infection and latency formation in CD4+ T cells. An answer to this question will improve 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 |
