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 productive infection of HIV in resting CD4+ T cells and might play a significant role in latency formation in these cells. The overall goal of this study is to investigate the roles of endothelial cells on HIV-1 infection and latency in resting CD4+ T cells.
The specific aims are 1) to investigate the effect of endothelial cells on HIV latency formation in resting CD4+ T cells using a newly developed in vitro long-lived primary T cell system; 2) to examine reactivation of latent HIV by endothelial cells using patient samples and in- vitro-generated latently infected resting CD4+ T cells;latently infected resting CD4+ T cells from patients or from in vitro generation will be co-cultured with endothelial cells to examine reactivation of proviruses. 3) to identify cellular factors potentially involved in allowing HIV infection in endothelial-cell- stimulated resting T cells using western blots. 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 eradication of HIV-1 diseases is the latent viral reservoir in resting CD4+ T cells. The proposed study aims to determine the roles endothelial cells play on HIV-1 infection and latency in resting CD4+ T cells. 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 |
