Peripheral and tissue-resident gamm/delta T cells in HIV latency

项目总结

Project Summary Identification and description of all cellular reservoirs of persistent HIV infection is of crucial importance to HIV eradication efforts. There is increasing evidence of the existence of additional latent reservoirs in the peripheral blood, and also within the tissue where a substantial fraction of the total lymphocytes of the body are located. We have discovered that a subclass of γδ T cells that express the Vδ2 TCR chain, harbor latent but replication-competent HIV. Furthermore, we have described a mechanism to explain Vδ2 cell infection, showing that although these cells generally express extremely low levels of the CD4 receptor, they can upregulate the CD4 receptor following stimuli in vitro. We have confirmed this finding by the discovery that acutely HIV-infected patients studied less than three weeks after infection, are found to have substantial expression of the CD4 receptor on Vδ2 cells. We propose to validate and clarify the importance of this new latent HIV reservoir within γδ T cells by i) extending our studies to include the complementary Vδ1 TCR γδ T cell population, as we find significant levels of HIV DNA within this second γδ T cell population, ii) studying infection and latency within γδ T cells in the gut associated lymphoid tissue (GALT), lymphoid tissues (LT) and liver, given the predominance of γδ T cells within these tissues, iii) analyze the stability and durability of latency within the γδ T cell reservoir, and iv) explore therapeutic approaches to disrupt latency within γδ T cells. Our investigations will contribute critically to the effort to define and eradicate HIV infection within all persistent, latently infected cells.